[4-(6-HALO-7-Substituted-2,4-DIOXO-1,4-DIHYDRO-2H-QUINAZOLIN-3-YL)-PHENYL]-5-CHLORO-THIOPHEN-2-YL-SULFONYLUREAS and Forms and Methods Related Thereto

ABSTRACT

The present invention provides novel sulfonylurea compounds of formula (I) and pharmaceutically acceptable derivatives and polymorph and amorphous forms thereof. The compounds in their various forms are effective platelet ADP receptor inhibitors and may be used in various pharmaceutical compositions, and are particularly effective for the prevention and/or treatment of cardiovascular diseases, particularly those diseases related to thrombosis. The invention also provides a method for preparing such compounds and forms and for preventing or treating thrombosis and thrombosis related conditions in a mammal comprising the step of administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or forms thereof.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation application of pending U.S. patentapplication Ser. No. 11/556,490, filed Nov. 3, 2006 which claimspriority under 35 U.S.C. §119(e) from U.S. Provisional Application60/733,650, filed Nov. 3, 2005, which are each incorporated by referencein their entireties herewith.

BACKGROUND OF THE INVENTION

Thrombotic complications are a major cause of death in theindustrialized world. Examples of these complications include acutemyocardial infarction, unstable angina, chronic stable angina, transientischemic attacks, strokes, peripheral vascular disease,preeclampsia/eclampsia, deep venous thrombosis, embolism, disseminatedintravascular coagulation and thrombotic cytopenic purpura. Thromboticand restenotic complications also occur following invasive procedures,e.g., angioplasty, carotid endarterectomy, post CABG (coronary arterybypass graft) surgery, vascular graft surgery, stent placements andinsertion of endovascular devices and prostheses, and hypercoagulablestates related to genetic predisposition or cancers. It is generallythought that platelet aggregates play a critical role in these events.Blood platelets, which normally circulate freely in the vasculature,become activated and aggregate to form a thrombus from disturbed bloodflow caused by ruptured atherosclerotic lesions or by invasivetreatments such as angioplasty, resulting in vascular occlusion.Platelet activation can be initiated by a variety of agents, e.g.,exposed subendothelial matrix molecules such as collagen, or by thrombinwhich is formed in the coagulation cascade.

An important mediator of platelet activation and aggregation is ADP(adenosine 5′-diphosphate) which is released from blood platelets in thevasculature upon activation by various agents, such as collagen andthrombin, and from damaged blood cells, endothelium or tissues.Activation by ADP results in the recruitment of more platelets andstabilization of existing platelet aggregates. Platelet ADP receptorsmediating aggregation are activated by ADP and some of its derivativesand antagonized by ATP (adenosine 5′-triphosphate) and some of itsderivatives (Mills, D. C. B. (1996) Thromb. Hemost. 76:835-856).Therefore, platelet ADP receptors are members of the family of P2receptors activated by purine and/or pyrimidine nucleotides (King, B.F., Townsend-Nicholson, A. & Burnstock, G. (1998) Trends Pharmacol. Sci.19:506-514).

Recent pharmacological data using selective antagonists suggests thatADP-dependent platelet aggregation requires activation of at least twoADP receptors (Kunapuli, S. P. (1998), Trends Pharmacol Sci. 19:391-394;Kunapuli, S. P. & Daniel, J. L. (1998) Biochem. J. 336:513-523; Jantzen,H. M. et al. (1999) Thromb. Hemost. 81:111-117). One receptor appears tobe identical to the cloned P2Y₁ receptor, mediates phospholipase Cactivation and intracellular calcium mobilization and is required forplatelet shape change. The second platelet ADP receptor important foraggregation mediates inhibition of adenylyl cyclase. Based on itspharmacological and signaling properties this receptor has beenprovisionally termed P2Y_(ADP) (Fredholm, B. B. et al. (1997) TIPS18:79-82), P2T_(AC) (Kunapuli, S. P. (1998), Trends Pharmacol. Sci.19:391-394) or P2Ycyc (Hechier, B. et al. (1998) Blood 92, 152-159).More recently, molecular cloning of this receptor (Hollopeter, G. et al.(2001) Nature 409: 202-207) has revealed that it is a new member of theG-protein coupled family and is the target of the thienopyridine drugsticlopidine and clopidogrel. The nomenclature given to this receptor isP2Y₁₂.

Various directly or indirectly acting synthetic inhibitors ofADP-dependent platelet aggregation with antithrombotic activity havebeen reported. The orally active antithrombotic thienopyridinesticlopidine and clopidogrel inhibit ADP-induced platelet aggregation,binding of radiolabeled ADP receptor agonist 2-methylthioadenosine5′-diphosphate to platelets, and other ADP-dependent events indirectly,probably via formation of an unstable and irreversible acting metabolite(Quinn, M. J. & Fitzgerald, D. J. (1999) Circulation 100:1667-1667).Some purine derivatives of the endogenous antagonist ATP, e.g., AR-C(formerly FPL or ARL) 67085MX and AR-C69931Mx, are selective plateletADP receptor antagonists which inhibit ADP-dependent plateletaggregation and are effective in animal thrombosis models (Humphries etal. (1995), Trends Pharmacol. Sci. 16, 179; Ingall, A. H. et al. (1999)J. Med. Chem. 42, 213-230). Novel triazolo[4,5-d]pyrimidine compoundshave been disclosed as P_(2T)-antagonists (WO 99/05144). Tricycliccompounds as platelet ADP receptor inhibitors have also been disclosedin WO 99/36425. The target of these antithrombotic compounds appears tobe P₂Y₁₂, the platelet ADP receptor mediating inhibition of adenylylcyclase.

Despite these compounds, there exists a need for more effective plateletADP receptor inhibitors. In particular, there is a need for platelet ADPreceptor inhibitors having antithrombotic activity that are useful inthe prevention and/or treatment of cardiovascular diseases, particularlythose related to thrombosis.

In addition, while biological activity is a sine non qua for aneffective drug, the compound must be capable of large scalemanufacturing and the physical properties of the compound can markedlyimpact the effectiveness and cost of a formulated active ingredient.Salts of acidic and basic compounds can alter or improve the physicalproperties of a parent compound. These salt forming agents, however,must be identified empirically by the pharmaceutical chemist since thereis no reliable method to predict the influence of a salt species on thebehavior of a parent compound in dosage forms. Effective screeningtechniques, which potentially could simplify the selection process, areunfortunately absent (G. W. Radebaugh and L. J. Ravin Preformulation.In, Remington: The Science and Practice of Pharmacy; A. R. Gennaro Ed.;Mack Publishing Co. Easton, Pa., 1995; pp 1456-1457).

Amorphous and different crystalline solid/polymorphic forms of salts arefrequently encountered among pharmaceutically useful compounds.Polymorphism is the ability of any element or compound to crystallize asmore than one distinct crystalline species. Physical propertiesincluding solubility, melting point/endotherm maximum, density,hardness, crystalline shape and stability can be quite different fordifferent forms of the same chemical compound.

Crystalline solid and amorphous forms may be characterized by scatteringtechniques, e.g., x-ray diffraction powder pattern, by spectroscopicmethods, e.g., infra-red, solid state ¹³C and ¹⁹F nuclear magneticresonance spectroscopy and by thermal techniques, e.g, differentialscanning calorimetry or differential thermal analysis. Although theintensities of peaks in the x-ray powder diffraction patterns ofdifferent batches of a compound may vary slightly, the peaks and thepeak locations are characteristic for a specific crystalline solid oramorphous form. Additionally, infrared, Raman and thermal methods havebeen used to analyze and characterize crystalline and solid amorphousforms. Solid and amorphous forms may be characterized by data from theX-ray powder diffraction pattern determined in accordance withprocedures which are known in the art (see J. Haleblian, J. Pharm. Sci.1975 64:1269-1288, and J. Haleblain and W. McCrone, J. Pharm. Sci. 196958:911-929). Although the intensities of peaks in the x-ray powderdiffraction patterns of different batches of the compounds may varyslightly, the peaks and the peak locations are characteristic for aspecific crystalline solid form.

The problem which must be solved is to identify a suitable salt and formwhich (i) possesses adequate chemical stability during the manufacturingprocess, (ii) is efficiently prepared, purified and recovered, (ii)provides acceptable solubility in pharmaceutically acceptable solvents,(iii) is amenable to manipulation (e.g. flowability and particle size)and formulation with negligible decomposition or change of the physicaland chemical characteristics of the compound, (iv) exhibits acceptablechemical stability in the formulation. In addition, salts and formscontaining a high molar percent of the active ingredient are highlydesirable since they minimize the quantity of material which must beformulated and administered to produce a therapeutically effective dose.These often conflicting requirements make identification suitable saltsa challenging and important problem which must be solved by the skilledpharmaceutical scientist before drug development can proceed in earnest.

Therefore, there is a need for compounds and salts and amorphous andcrystalline solid forms of these compounds of the invention and anefficient process for producing the compounds, salts and crystallinesolid forms of the compounds of the invention. Solutions to the abovedifficulties and deficiencies are needed before compounds becomeeffective for routine treatment of thrombosis.

Polyaryl compounds generally are highly crystalline, poorly watersoluble and hydrophobic, resulting in difficulties in the preparation ofpharmaceutical formulations and problems associated withbioavailability. Accordingly, efforts were made to discover other formsof compounds of the invention and to investigate the properties thereof.There were discovered crystalline solid forms of salts of compounds ofthe invention. The present invention fulfills the above needs byproviding polymorphs and methods for treating and preventing thrombosis,while presenting a better adverse effect profile.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides compounds having theformula (I):

wherein:R¹ is selected from the group consisting of H, halogen, —OH,—C₁₋₁₀-alkyl and C₁₋₆-alkylamino; andX is selected from the group consisting of: F and I.

The invention also covers all pharmaceutically acceptable derivatives ofthe compounds of formula (I).

In another aspect, the invention provides crystalline solid andamorphous forms of the potassium and sodium salts of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea.

In another aspect, the invention provides pharmaceutical compositionsfor preventing or treating thrombosis and thrombosis related conditionsin a mammal. The compositions contain a therapeutically effective amountof one or more compounds of formula (I) or a pharmaceutically acceptablesalt thereof and a pharmaceutically acceptable carrier or excipient. Theinvention further provides a method for preventing or treatingthrombosis and thrombosis related conditions in a mammal byadministering a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt thereof.

In still another aspect, the present invention provides methods forpreparing compounds of formula (I), their crystalline solid andamorphous forms and pharmaceutical compositions for preventing ortreating thrombosis and thrombosis related conditions in a mammal.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides structure of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureapotassium and/or sodium salt.

FIG. 2 a shows an X-ray powder diffraction (XRPD) of crystalline solidform A of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureapotassium salt dihydrate. FIG. 2 b shows an XRPD of crystalline solidform A of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureapotassium salt dihydrate showing peak information.

FIG. 3 a shows an XRPD of crystalline solid form B of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureapotassium salt. FIG. 3 b shows an XRPD of crystalline solid form B of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureapotassium salt showing peak information.

FIG. 4 shows an XRPD of the amorphous form of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureasodium salt.

FIG. 5 shows a Fourier-transformed infrared spectra (FT-IR) ofcrystalline solid form A of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureapotassium salt dihydrate.

FIG. 6 shows a Fourier-transformed infrared spectra (FT-IR) ofcrystalline solid form B of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureapotassium salt dihydrate.

FIG. 7 shows the FT-IR of an amorphous form of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureasodium salt.

FIG. 8 shows the ¹H-NMR of crystalline solid form A of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureapotassium salt dihydrate.

FIG. 9 shows the ¹H-NMR of crystalline solid form B of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureapotassium salt.

FIG. 10 shows the ¹H-NMR of amorphous form of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureasodium salt.

FIG. 11 provides the gravimetric vapour sorption (GVS) data ofcrystalline solid form A of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureapotassium salt dihydrate.

FIG. 12 a provides the gravimetric vapour sorption (GVS) data ofcrystalline solid form B of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureapotassium salt dihydrate. The sample was recovered after the completionof the GVS experiment and re-examined by XRPD. The results (FIG. 12 b)show that no phase change has occurred over the course of the GVSexperiment. The change in intensity of the peak at ca. 5.4° 2θ, is apreferred orientation effect.

FIG. 13 provides the gravimetric vapour sorption (GVS) data of amorphousform of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureasodium salt.

FIG. 14 provides the differential scanning calorimetry (DSC) data ofcrystalline solid form A of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureapotassium salt dihydrate.

FIG. 15 provides the TGA data of crystalline solid form A of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureapotassium salt dihydrate.

FIG. 16 provides the DSC data of crystalline solid form B of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureapotassium salt.

FIG. 17 provides the TGA data of crystalline solid form B of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureapotassium salt.

FIG. 18 provides the DSC data of amorphous form of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureasodium salt.

FIG. 19 provides the TGA data of amorphous form of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureasodium salt.

DETAILED DESCRIPTION OF THE INVENTION

The present invention involves sulfonylurea compounds and theirderivatives and crystalline solid and amorphous forms thereof, and theirpreparation. The potassium salt of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureahas excellent crystallinity, stability and purity. The compounds of thepresent invention are useful for the treatment and prevention ofundesired thrombosis and thrombosis related conditions in mammals.

I. Definitions

In accordance with the present invention and as used herein, thefollowing terms are defined with the following meanings, unlessexplicitly stated otherwise.

The phrase “a” or “an” entity as used herein refers to one or more ofthat entity; for example, a compound refers to one or more compounds orat least one compound. As such, the terms “a” (or “an”), “one or more”,and “at least one” can be used interchangeably herein.

The phrase “about” as used herein means variation one might see inmeasurements taken among different instruments, samples, and samplepreparations. Such variation may include, for instance, colligativeproperties for thermal measurements. Typical variation among differentx-ray diffractometers and sample preparations for crystalline solidforms is on the order of 0.2°2θ. Typical variation for Raman and IRspectrometers is on the order of twice the resolution of thespectrometer. The resolution of the spectrometer used was about 2 cm⁻¹.

The term “solvate” as used herein means a compound of the invention or asalt, thereof, that further includes a stoichiometric ornon-stoichiometric amount of a solvent bound by non-covalentintermolecular forces in an amount of greater than about 0.3% whenprepared according to the invention.

The term “hydrate” as used herein means a compound of the invention or asalt thereof, that further includes a stoichiometric ornon-stoichiometric amount of water bound by non-covalent intermolecularforces. Hydrates are formed by the combination of one or more moleculesof water with one of the substances in which the water retains itsmolecular state as H₂O, such combination being able to form one or morehydrate.

The term “anhydrous” as used herein means a compound of the invention ora salt thereof that contains less than about 3% by weight water orsolvent when prepared according to the invention.

The term “drying” as used herein means a method of removing solventand/or water from a compound of the invention which, unless otherwisespecified, may be done at atmospheric pressure or under reduced pressureand with or without heating until the level of solvent and/or watercontained reached an acceptable level.

The term “polymorphs” as used herein means crystal structures in which acompound can crystallize in different crystal packing arrangements, allof which have the same elemental composition. Different crystal formsusually have different X-ray diffraction patterns, infrared spectra,melting points/endotherm maximums, density hardness, crystal shape,optical and electrical properties, stability and solubility.Recrystallization solvent, rate of crystallization, storage temperature,and other factors may cause one crystal form to dominate.

The term “solid form” as used herein means crystal structures in whichcompounds can crystallize in different packing arrangements. Solid formsinclude polymorphs, hydrates, and solvates as those terms are used inthis invention. Different solid forms, including different polymorphs,of the same compound exhibit different x-ray powder diffraction patternsand different spectra including infra-red, Raman, and solid-state NMR.Their optical, electrical, stability, and solubility properties may alsodiffer.

The term “characterize” as used herein means to select data from ananalytical measurement such as X-ray powder diffraction, infra-redspectroscopy, Raman spectroscopy, and/or solid-state NMR to distinguishone solid form of a compound from other solid forms of a compound.

The term “mammal” includes, without limitation, humans, domestic animals(e.g., dogs or cats), farm animals (cows, horses, or pigs), monkeys,rabbits, mice, and laboratory animals.

The term “alkyl” refers to saturated aliphatic groups includingstraight-chain, branched-chain and cyclic groups having the number ofcarbon atoms specified, or if no number is specified, having up to about12 carbon atoms. Examples of alkyl groups include methyl, ethyl,n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl,n-hexyl, n-heptyl, n-octyl, and the like.

The terms “alkoxy,” “alkylamino” and “alkylthio” (or thioalkoxy) areused in their conventional sense, and refer to those alkyl groupsattached to the remainder of the molecule via an oxygen atom, an aminogroup, or a sulfur atom, respectively. For brevity, the termC₁₋₆alkylamino is meant to include straight chain, branched or cyclicalkyl groups or combinations thereof, such as methyl, ethyl,2-methylpropyl, cyclobutyl and cyclopropylmethyl.

The term “C₁-C₆ alkylamino” or “C₁₋₆ alkylamino” as used herein refersto an amino moiety attached to the remainder of the molecule whereby thenitrogen is substituted with one or two C₁₋₆ alkyl substituents, asdefined above.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl,” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“C₁₋₄ haloalkyl” is mean to include trifluoromethyl,2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

The term “pharmaceutically acceptable derivatives” is meant to includesalts of the active compounds which are prepared with relativelynontoxic acids or bases, depending on the particular substituents foundon the compounds described herein. When compounds of the presentinvention contain relatively acidic functionalities, base addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include those derived from inorganic bases such as sodium,potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper,manganese, aluminum salts and the like. Particularly preferred are thepotassium and sodium salts. Salts derived from pharmaceuticallyacceptable organic nontoxic bases include salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperazine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particularly preferredorganic nontoxic bases are isopropylamine, diethylamine, ethanolamine,trimethamine, dicyclohexylamine, choline, and caffeine. When compoundsof the present invention contain relatively basic functionalities, acidaddition salts can be obtained by contacting the neutral form of suchcompounds with a sufficient amount of the desired acid, either neat orin a suitable inert solvent. Examples of pharmaceutically acceptableacid addition salts include those derived from inorganic acids likehydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic,phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, malonic, benzoic, succinic, suberic,fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric,tartaric, methanesulfonic, and the like. Also included are salts ofamino acids such as arginate and the like, and salts of organic acidslike glucuronic or galactunoric acids and the like (see, for example,Berge, S. M., et al, “Pharmaceutical Salts”, Journal of PharmaceuticalScience, 1977, 66, 1-19; Bundgaard, H., ed., Design of Prodrugs(Elsevier Science Publishers, Amsterdam 1985)). Certain specificcompounds of the present invention contain both basic and acidicfunctionalities that allow the compounds to be converted into eitherbase or acid addition salts.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present invention.

In addition to salt forms, the term “pharmaceutically acceptablederivatives” is meant to include compounds which are in a prodrug form.“Prodrugs” of the compounds described herein are those compounds thatreadily undergo chemical changes under physiological conditions toprovide the compounds of the present invention. Additionally, prodrugscan be converted to the compounds of the present invention by chemicalor biochemical methods in an ex vivo environment. For example, prodrugscan be slowly converted to the compounds of the present invention whenplaced in a transdermal patch reservoir with a suitable enzyme orchemical reagent (see Bundgaard, H., ed., Design of Prodrugs (ElsevierScience Publishers, Amsterdam 1985)).

“Pharmaceutically acceptable ester” refers to those esters which retain,upon hydrolysis of the ester bond, the biological effectiveness andproperties of the carboxylic acid or alcohol and are not biologically orotherwise undesirable. For a description of pharmaceutically acceptableesters as prodrugs, see Bundgaard, H., supra. These esters are typicallyformed from the corresponding carboxylic acid and an alcohol. Generally,ester formation can be accomplished via conventional synthetictechniques. (See, e.g., March Advanced Organic Chemistry, 3rd Ed., p.1157 (John Wiley & Sons, New York 1985) and references cited therein,and Mark et al., Encyclopedia of Chemical Technology, (1980) John Wiley& Sons, New York). The alcohol component of the ester will generallycomprise: (i) a C₂-C₁₂ aliphatic alcohol that can or can not contain oneor more double bonds and can or can not contain branched carbons; or(ii) a C₇-C₁₂ aromatic or heteroaromatic alcohols. The present inventionalso contemplates the use of those compositions which are both esters asdescribed herein and at the same time are the pharmaceuticallyacceptable acid addition salts thereof.

“Pharmaceutically acceptable amide” refers to those amides which retain,upon hydrolysis of the amide bond, the biological effectiveness andproperties of the carboxylic acid or amine and are not biologically orotherwise undesirable. For a description of pharmaceutically acceptableamides as prodrugs, see, Bundgaard, H., ed., supra. These amides aretypically formed from the corresponding carboxylic acid and an amine.Generally, amide formation can be accomplished via conventionalsynthetic techniques. See, e.g., March et al., Advanced OrganicChemistry, 3rd Ed., p. 1152 (John Wiley & Sons, New York 1985), and Market al., Encyclopedia of Chemical Technology, (John Wiley & Sons, NewYork 1980). The present invention also contemplates the use of thosecompositions which are both amides as described herein and at the sametime are the pharmaceutically acceptable acid addition salts thereof.

The term “pharmaceutically acceptable derivatives” is also meant toinclude compounds of the present invention which can exist in unsolvatedforms as well as solvated forms, including hydrated forms. In general,the solvated forms are equivalent to unsolvated forms and are intendedto be encompassed within the scope of the present invention. Certaincompounds of the present invention may exist in multiple crystalline oramorphous forms. In general, all physical forms are equivalent for theuses contemplated by the present invention and are intended to be withinthe scope of the present invention.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers and individual isomers (e.g., separate enantiomers)are all intended to be encompassed within the scope of the presentinvention.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I) or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areintended to be encompassed within the scope of the present invention.

“Biological property” for the purposes herein means an in vivo effectoror antigenic function or activity that is directly or indirectlyperformed by a compound of this invention that are often shown by invitro assays. Effector functions include receptor or ligand binding, anyenzyme activity or enzyme modulatory activity, any carrier bindingactivity, any hormonal activity, any activity in promoting or inhibitingadhesion of cells to an extracellular matrix or cell surface molecules,or any structural role. Antigenic functions include possession of anepitope or antigenic site that is capable of reacting with antibodiesraised against it.

As used herein, the term “preventing” refers to the prophylactictreatment of a patient in need thereof. The prophylactic treatment canbe accomplished by providing an appropriate dose of a therapeutic agentto a subject at risk of suffering from an ailment, thereby substantiallyaverting onset of the ailment.

As used herein, the term “treating” refers to providing an appropriatedose of a therapeutic agent to a subject suffering from an ailment.

As used herein, the term “therapeutically effective amount” refers to anamount of a therapeutic agent that is sufficient to affect the treatmentof a subject suffering from an ailment.

As used herein, the term “condition” refers to a disease state for whichthe compounds, compositions and methods of the present invention arebeing used against.

As used herein, the term “ADP-mediated disease or condition” and thelike refers to a disease or condition characterized by less than orgreater than normal, ADP activity. A ADP-mediated disease or conditionis one in which modulation of ADP results in some effect on theunderlying condition or disease (e.g., a ADP inhibitor or antagonistresults in some improvement in patient well-being in at least somepatients).

As used herein, the term “blood sample” refers to whole blood taken froma subject, or any fractions of blood including plasma or serum.

In the compounds of this invention, carbon atoms bonded to fournon-identical substituents are asymmetric. Accordingly, the compoundsmay exist as diastereoisomers, enantiomers or mixtures thereof. Thesyntheses described herein may employ racemates, enantiomers ordiastereomers as starting materials or intermediates. Diastereomericproducts resulting from such syntheses may be separated bychromatographic or crystallization methods, or by other methods known inthe art. Likewise, enantiomeric product mixtures may be separated usingthe same techniques or by other methods known in the art. Each of theasymmetric carbon atoms, when present in the compounds of thisinvention, may be in one of two configurations (R or S) and both arewithin the scope of the present invention.

II. Compound Embodiments of the Invention

Compounds of formula (I) below represent one embodiment of theinvention:

wherein:

X is selected from the group consisting of F and I;R¹ is selected from the group consisting of H, halogen, —OH,—C₁₋₁₀-alkyl and C₁₋₆-alkylamino.

The invention also covers all pharmaceutically acceptable derivatives ofthe compounds of formula I. Pharmaceutically acceptable salts can beprepared using at least one inorganic or organic base including, but notlimited to potassium hydride, potassium hydroxide, potassium alkoxides,sodium hydride, sodium hydroxide, sodium alkoxides and the like.

Within the descriptions above are a number of preferred embodiments. Inone group of preferred embodiments, R¹ is C₁₋₁₀-alkyl orC₁₋₆-alkylamino.

In another group of preferred embodiments, R¹ is C₁₋₆-alkylamino. In yetanother group of preferred embodiments, X is F.

A number of specific compounds are among the most preferred embodimentsfor the compounds of formula I, and are provided in FIG. 1 and alsorepresented below.

In one preferred embodiment of the invention, compounds of formula (I)include the compound having the formula:

Another group of particularly preferred compounds of the invention havethe formula:

III. Preparation of Compounds of the Invention

Scheme 1 illustrates a method of preparing certain compounds of formulaI wherein Ar is phenylene and R¹ and X¹ are as described above.

A compound of formula I can be prepared by reducing 2-nitro-benzoic acidmethyl ester compound 1 by procedures known to one skilled in the art toyield aniline 2. (See also published patent application US 2002/077486).For example, a method of nitro group reduction can be carried out byhydrogenation. The hydrogenation is carried out with a suitable catalyst(e.g., 10% Pd/C or Pt(s)/C) under hydrogen and in an appropriatesolvent, typically in an alcohol, preferably ethanol at roomtemperature. Treating compound 2 with appropriately substituted arylisocyanate (Method A) provides intermediate urea 3a. Alternatively, urea3a can be formed by treating compound 2 with triphosgene in the presenceof a base such as triethylamine or diisopropylethylamine in an inertsolvent such as THF, dichloromethane and MeCN at appropriatetemperature, preferably at 20° C., followed by substituted aniline(Method B). Urea 3a, prepared by Method A or Method B typically withoutfurther purification can be subjected to thermal or base (such asN-methyl morpholine (NMM) or polystyrene-NMM (PS-NMM) induced ringclosure to provide quinazolinedione 4a. The nitro group of compound 4acan be reduced by procedures known to one skilled in the art to yieldfree amino group. For example, a method of reduction can be carried outby hydrogenation, with a suitable catalyst (e.g., 10% palladium oncarbon) in an appropriate solvent, typically an alcohol. The formationof sulfonylurea linkage can be accomplished by treating the reducedproduct aniline 5a with a pre-mixed solution of substitutedthiophene-2-sulfonamide, N,N′-disuccinimidyl carbonate andtetramethylguanidine in dichloromethane, followed by treatment with TFAin dichloromethane at room temperature to afford the sulfonylurea offormula I. Alternatively, the sulfonylurea linkage can be formed byreacting the aniline 5a and 5-Chloro-thiophene-2-sulfonyl ethylcarbamatein suitable solvents, which include, but are not limited to, toluene,acetonitrile, 1,4-dioxane and DMSO.

Scheme 2 illustrates an alternative method of preparing compounds ofFormula I wherein R¹ is, for example, alkylamino and L¹ is halogen,alkylsulfonate, haloalkylsulfonate and arylsulfonate.

The urea 3b can be prepared by treating compound 2 with triphosgene orp-nitrophenyl chloroformate in the presence of a base, such astriethylamine and/or diisopropylethylamine, in an inert solvent, such asTHF, dichloromethane and/or MeCN, at an appropriate temperature,typically at about 20° C., followed by treatment with an appropriatelyprotected aniline (Method B). Urea 3b, typically without furtherpurification, can be subjected to base induced ring closure to provideintermediate quinazolinedione 4b. The protecting group of compound 4bcan be removed using standard techniques appropriate for the protectinggroup used. For example a BOC protecting group can be removed bytreating compound 4b with 4N HCl in dioxane. The C-7 fluoro of compound5b is then displaced by treatment with methylamine in DMSO at about 120°C. to afford aniline 6a. The preparation of target sulfonylurea 7a canbe accomplished by treating aniline 6a with5-chloro-thiophene-2-sulfonyl ethylcarbamate in an appropriate solvent,such as dimethyl sulfoxide, dioxane and/or acetonitrile with heating.

Scheme 3 illustrates an alternative method of preparing compounds ofFormula I wherein R¹ is, for example, alkylamino and L¹ is halogen,alkylsulfonate, haloalkylsulfonate and arylsulfonate and M is K.

The urea 3a can be prepared by treating compound 2 withp-nitrophenylchloroformate, in an inert solvent, such as THF,dichloromethane and/or MeCN, at an appropriate temperature, typically atabout 20° C., followed by treatment with an appropriately protectedaniline (Method B). According to the invention, compounds of formula (I)may be further treated to form pharmaceutically acceptable salts e.g.7a. Treatment of a compound of the invention with an acid or base mayform, respectively, a pharmaceutically acceptable acid addition salt anda pharmaceutically acceptable base addition salt, each as defined above.Various inorganic and organic acids and bases known in the art includingthose defined herein may be used to effect the conversion to the salt.

Compounds of formula (I) may be isolated using typical isolation andpurification techniques known in the art, including, for example,chromatographic and recrystallization methods.

In compounds of formula (I) of the invention, carbon atoms of R¹ towhich four non-identical substituents are bonded are asymmetric.Accordingly, a compound of formula (I) may exist as enantiomers,diastereomers or a mixture thereof. The enantiomers and diastereomersmay be separated by chromatographic or crystallization methods, or byother methods known in the art. The asymmetric carbon atom when presentin a compound of formula (I) of the invention, may be in one of twoconfigurations (R or S) and both are within the scope of the invention.The presence of small amounts of the opposing enantiomer or diastereomerin the final purified product does not affect the therapeutic ordiagnostic application of such compounds.

According to the invention, compounds of formula (I) may be furthertreated to form pharmaceutically acceptable salts. Treatment of acompound of the invention with an acid or base may form, respectively, apharmaceutically acceptable acid addition salt and a pharmaceuticallyacceptable base addition salt, each as defined above. Various inorganicand organic acids and bases known in the art including those definedherein may be used to effect the conversion to the salt.

The invention also provides pharmaceutically acceptable isomers,hydrates, and solvates of compounds of formula (I). Compounds of formula(I) may also exist in various isomeric and tautomeric forms includingpharmaceutically acceptable salts, hydrates and solvates of such isomersand tautomers. For example, while some compounds are provided herein asdihydrates having two molecules of water per molecule of the compound offormula (I), the present invention also provides compounds that areanhydrous, monohydrates, trihydrates, sesquihydrates, and the like.

This invention also encompasses prodrug derivatives of the compounds offormula (I). The term “prodrug” refers to a pharmacologically inactivederivative of a parent drug molecule that requires biotransformation,either spontaneous or enzymatic, within the organism to release theactive drug. Prodrugs are variations or derivatives of the compounds offormula (I) of this invention which have groups cleavable undermetabolic conditions. Prodrugs become the compounds of the inventionwhich are pharmaceutically active in vivo when they undergo solvolysisunder physiological conditions or undergo enzymatic degradation. Prodrugcompounds of this invention may be called single, double, triple, etc.,depending on the number of biotransformation steps required to releasethe active drug within the organism, and indicating the number offunctionalities present in a precursor-type form. Prodrug forms oftenoffer advantages of solubility, tissue compatibility, or delayed releasein the mammalian organism (Bundgard, Design of Prodrugs, pp. 7-9, 21-24,Elsevier, Amsterdam (1985); Silverman, The Organic Chemistry of DrugDesign and Drug Action, pp. 352-401, Academic Press, San Diego, Calif.(1992)). Prodrugs commonly known in the art include acid derivativeswell known to practitioners of the art, such as, for example, estersprepared by reaction of the parent acids with a suitable alcohol, oramides prepared by reaction of the parent acid compound with an amine,or basic groups reacted to form an acylated base derivative. Moreover,the prodrug derivatives of this invention may be combined with otherfeatures herein taught to enhance bioavailability.

IV. Crystalline Solid and Amorphous Embodiments of the Invention andTheir Preparation

The present invention also provides crystalline solid and/or amorphousforms of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureaand processes for their preparation and pharmaceutical compositionscomprising these forms. The potassium salt has the following generalformula:

and the sodium salt has the following general formula:

In developing a process for production of an active pharmaceuticalingredient (API), two factors are of great importance: the impurityprofile and the crystal morphology of the compound. The results from theinitial isolation and crystallization work showed a profile of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureaof 99.6%. Preferably the API has levels of impurities below 0.2% and isin the most thermodynamically stable crystalline solid form. Theisolation and crystallization work indicated that there was at least twocrystalline solid forms of the potassium salt of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea(designated as Form A and B) and an amorphous form of the sodium salt of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea.

The solid forms of the invention may be described by one or more ofseveral techniques including X-ray powder diffraction, Ramanspectroscopy, IR spectroscopy, and thermal methods. Further,combinations of such techniques may be used to describe the invention.For example, one or more X-ray powder diffraction peaks combined withone or more Raman peaks may be used to describe one or more solid formsof the invention in a way that differentiates it from the other solidforms.

Although it characterizes a form, it is not necessary to rely only uponan entire diffraction pattern or spectrum to characterize a solid form.Those of ordinary skill in the pharmaceutical arts recognize that asubset of a diffraction pattern or spectrum may be used to characterizea solid form provided that subset distinguishes the solid form from theother forms being characterized. Thus, one or more X-ray powderdiffraction peaks alone may be used to characterize a solid form.Likewise, one or more IR peaks alone or Raman peaks alone may be used tocharacterize a solid form. Such characterizations are done by comparingthe X-ray, Raman, and IR data amongst the forms to determinecharacteristic peaks.

One may also combine data from other techniques in such acharacterization. Thus, one may rely upon one or more peaks from anx-ray powder diffraction and for example, Raman or IR data, tocharacterize a form. For example, if one or more x-ray peakscharacterize a form, one could also consider Raman or IR data tocharacterize the form. It is sometimes helpful to consider Raman data,for example, in pharmaceutical formulations.

The polymorphs were identified from by using two differentcrystallization conditions. (1) Crystalline form A was isolated aftercrystallization of the crude wet-cake from methanol and drying the crudewet-cake to effect solvent removal, and (2) crystalline solid form B wasformed from crystallization from EtOH/H₂O or by trituration withmethanol.

The potassium salt was suspended in methanol and then heated until aclear solution was observed. This was followed by cooling and theresulting crystalline solid was isolated and dried at room temperatureunder reduced pressure to give the morphologically distinct crystallinesolid potassium salt/form A. FIGS. 14 and 2 respectively show the DSCtrace and the X-ray powder pattern for the crystalline solid.Differential scanning calorimetry (DSC) of Form A of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureapotassium salt defined a melt of desolvate at 238° C. A largedecomposition peak was recorded, onset temperature approximately 300° C.In the DSC trace, the sharpness of the completion of melt at about 246°C. is characteristic.

In the X-ray powder diffraction pattern, the peaks at about 9.5 and 25.5are the main features of the pattern (for a discussion of the theory ofX-ray powder diffraction patterns see “X-ray diffraction procedures” byH. P. Klug and L. E. Alexander, J. Wiley, New York (1974)). The peaks atabout 9.5° 2θ and 25.5° 2θ characterize Form A with respect to Form Bbecause Form B does not have peaks to within 0.2° 2θ, twice theapproximate precision of X-ray powder diffraction peaks, of the two FormA peaks. Because the typical variation in any given x-ray powderdiffraction peak is on the order of 0.2° 2θ, when selecting peaks tocharacterize a polymorph, one selects peaks that are at least twice thatvalue (i.e., 0.4° θ) from a peak from another polymorph. Thus, in aparticular polymorph x-ray pattern, a peak that is at least 0.4° θ froma peak in another polymorph is eligible to be considered as a peak thatcan either alone or together with another peak be used to characterizethat polymorph. Tables 1 and 2 identify the main peaks of Forms A and B.From that list, one sees that the peak at about 25.5° 2θ (on the tablelisted as 25.478°2θ), when taken to one decimal point, is greater than0.2° 2θ away from any peak in Forms B. Thus, the peak at about 25.5° 2θcan be used to distinguish Form A from Form B. The peak at about 9.5° 2θ(9.522°2θ in Table 1) is the most intense peak in the Form A X-raypowder diffraction pattern of FIG. 2 and is more than 0.2° 2θ away fromany peak in Form B. Thus, the Form A peaks at about 9.5° 2θ and 25.5° 2θcharacterize Form A with respect to Form B. The solid form isolated atthis stage in the process contained about 2 molecule of water to onemolecule of salt.

TABLE 1 Potassium Salt Form A XRPD Peak (°2θ) and % Intensity ListingData Tabulated from FIG. 2b. Intensity (%) Angle (°2-Theta) d value (Å)100.0 9.522 9.28049 35.0 25.478 3.49317 24.2 28.764 3.10110 22.5 27.1753.27877 20.1 19.090 4.64529 15.2 22.977 3.86744 14.4 24.630 3.61155 13.823.987 3.70680 12.3 15.530 5.70104 12.3 18.518 4.78751 12.1 18.1464.88482 9.5 16.223 5.45912 8.9 13.219 6.69229 8.7 21.040 4.21883 6.816.929 5.23304 5.6 4.822 18.31110

TABLE 2 Potassium Salt Form B XRPD Peak (°2θ) and % Intensity ListingData Tabulated from FIG. 3b. Intensity (%) Angle (°2-Theta) d value (Å)100.0 25.087 3.54667 70.4 20.328 4.36505 63.9 24.442 3.63878 52.9 5.33916.53922 50.9 19.594 4.52687 34.7 26.155 3.40428 30.6 17.37 5.10115 28.621.373 4.15387 28.1 14.526 6.09284 27.6 22.53 3.94319 26.5 9.921 8.9079426.5 21.729 4.08664 24.9 13.569 6.52011 23.6 15.346 5.76906 22.9 29.4783.02760 18.9 10.655 8.29583

Preferred orientation can affect peak intensities, but not peakpositions, in XRPD patterns. In the case of the potassium salts,preferred orientation has the most effect on the region at lower angles.Preferred orientation causes some peaks in this region to be diminished(or increased). Crystal habit does not clearly differentiate between thesolid forms; a variety of habits have been observed for each form,including needles, blades, plates, and irregular-shaped particles.

Thus in one embodiment, the present invention provides[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureapotassium salt in new crystalline forms designated as Form A and Form B.

Thus in one embodiment, the invention provides[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureapotassium salt in a crystalline solid form, including a substantiallypure form, which provides at least one of:

(i) an infra red spectrum substantially in accordance with FIG. 5;(ii) an X-ray powder diffraction pattern substantially in accordancewith FIG. 2; and(iii) a DSC scan substantially in accordance with FIG. 14; hereindesignated as Form A.

In another embodiment, the invention provides[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureapotassium salt in a crystalline solid form, including a substantiallypure form, which provides at least one of:

(i) an infra red spectrum comprising absorption peaks at about 3559,3389, 3324, 1698, 1623, 1563, 1510, 1448, 1431, 1403, 1383, 1308, 1269,1206, 1174, 1123, 1091, 1072, 1030, 987, 939, 909, 871, 842, 787, 780,769, 747, 718, 701, 690 and 667 cm⁻¹;(ii) an X-ray powder diffraction pattern comprising peaks at about 9.5and about 25.5°2θ; and(iii) a DSC maximum endotherm at about 246° C.;herein designated as Form A.

In another embodiment, the invention provides a crystalline polymorph of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureapotassium salt which provides an infra red spectrum containingabsorption peaks at about 3559, 3389, 3324, 1698, 1623, 1563, 1510,1448, 1431, 1403, 1383, 1308, 1269, 1206, 1174, 1123, 1091, 1072, 1030,987, 939, 909, 871, 842, 787, 780, 769, 747, 718, 701, 690 and 667 cm⁻¹;herein designated as Form A.

In another embodiment, the invention provides[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureapotassium salt in a crystalline solid form, including a substantiallypure form, which provides an X-ray powder diffraction pattern comprisingpeaks at about 9.5 and about 25.5°2θ herein designated as Form A.

In another embodiment, the invention provides[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureapotassium salt in a crystalline solid form, including a substantiallypure form, which provides a DSC endotherm maximum of about 246° C.;

herein designated as Form A.

In another embodiment, the invention provides a crystalline polymorph of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureapotassium salt which provides spectrum containing at least one, butfewer than the above peak listings, herein designated as Form A.

FIGS. 16 and 3 respectively show the DSC trace and the X-ray powderpattern for another crystalline solid. These results were observed whenthe remaining water was removed. In the DSC trace, a transition at about293° C. is noteworthy, because Form A melts at 246° C. The peaks atabout 20.3°2θ and 25.1° 2θ in the X-ray powder diffraction pattern alsocharacterize Form B with respect to Form A, because Form A does not havepeaks to within 0.2° 2θ, the approximate precision of X-ray powderdiffraction peaks, of the two characteristic Form B peaks (see Tables 1and 2). From that list, one sees that the peaks at about 20.3° 2θ and25.1° 2θ (in Table 2 listed as 20.328° 2θ and 25.087° 2θ, respectively),when taken to one decimal point, is greater than 0.2° 2θ away from anypeak in Form A. Thus, the peaks at about 20.3° 2θ and 25.1° 2θ can beused to distinguish Form B from Form A.

Thus in one embodiment, the invention provides[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureapotassium salt in a crystalline solid form, including a substantiallypure form, which provides at least one of:

(i) an infra red spectrum substantially in accordance with FIG. 6;(ii) an X-ray powder diffraction pattern substantially in accordancewith FIG. 3; and(iii) a DSC scan substantially in accordance with FIG. 16; hereindesignated as Form B.

In another embodiment, the invention provides[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureapotassium salt in a crystalline solid form, including a substantiallypure form, which (i) an infra red spectrum comprising absorption peaksat about 3584, 3327, 3189, 2935, 2257, 2067, 1979, 1903, 1703, 1654,1630, 1590, 1557, 1512, 1444, 1429, 1406, 1375, 1317, 1346, 1317, 1288,1276, 1243, 1217, 1182, 1133, 1182, 1133, 1093, 1072, 1033, 987, 943,907, 883, 845, 831, 805, 776, 727, 694 and 674 cm⁻¹; (ii) an X-raypowder diffraction pattern comprising peaks at about 20.3° 2θ and about25.1° 2θ; and

(iii) a DSC maximum endotherm at about 293° C.; herein designated asForm B.

In another embodiment, the invention provides[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureapotassium salt in a crystalline solid form, including a substantiallypure form, wherein the compound provides an X-ray powder diffractionpattern comprising peaks at about 20.3° 2θ and 25.1° 2θ; hereindesignated as Form B.

In another embodiment the present invention provides[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureasodium salt in an amorphous form.

In one embodiment, the invention provides a form of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureasodium salt which provides at least one of:

(i) an infra red spectrum in a mineral oil dispersion substantially inaccordance with FIG. 7;(ii) an X-ray powder diffraction pattern substantially in accordancewith FIG. 4; and(iii) a DSC scan substantially in accordance with FIG. 18; hereindesignated as amorphous form.

In another embodiment, the invention provides a form of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureasodium salt which provides an infra red spectrum containing absorptionpeaks at about 3560, 1711, 1632, 1556, 1512, 1445, 1407, 1375, 1309,1280, 1227, 1133, 1092, 1032, 987, 905, 781, 770 and 691 cm⁻¹; hereindesignated as amorphous form.

In another embodiment, the invention provides a crystalline polymorph of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureasalts which provides spectrum containing at least one, but fewer thanthe above peak listings for the designated forms.

Crystalline form A of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureapotassium salt is a dihydrate which is stable to 15% relative humidity(RH) at 25° C. but which rehydrates at 20% RH at 25° C. Polymorph A ofthe potassium salt has been found to be equally stable as the amorphousform of the sodium salt. No change in the chemical purity of either saltform was observed after one week when in accelerated stability tests athigh temperature (40° C.) and high relative humidity (75% RH). Anadvantage of the potassium crystalline form A is that it is lesshygroscopic than the amorphous form of the sodium salt which picksup >15% w/w water at 40% RH. Both Form A and B are stable. Form B of thepotassium salt is anhydrous and non-hygroscopic (difficult to form adehydrate form) Form B of the potassium salt retains a better physicalappearance and handling properties over a longer period of time. Animprovement in the physical appearance of a dosage form of a drugenhances both physician and patient acceptance and increases thelikelihood of success of the treatment.

Further embodiments of the invention include mixtures of the differentcrystalline solid forms, and the amorphous form, of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureaand its salts. Such mixtures include compositions comprising at leastone solid form or at least two solid forms selected from Form A, Form Band the amorphous form. Any of the analytical techniques describedherein may be used to detect the presence of the solid forms in suchcompositions. Detection may be done qualitatively, quantitatively, orsemi-quantitatively as those terms as used and understood by those ofskill in the solid-state analytical arts.

For these analyses, use of standard analytical techniques involvingreference standards may be used. Further, such methods may include useof techniques such as partial-lease squares in conjunction with adiffractive or spectroscopic analytical technique. These techniques mayalso be used in pharmaceutical compositions of the invention.

V. Preparation of Crystalline Solid and Amorphous Forms of the Invention

Furthermore, the present invention is directed to processes for thepreparation of crystalline solid and amorphous forms of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureapotassium and sodium salts.

Crystalline solid and amorphous forms of the compounds of the inventionmay be prepared by various methods as outlined below. Other well-knowncrystallization procedures as well as modification of the proceduresoutline above may be utilized.

In another embodiment of the present invention there is provided[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureapotassium salt in a crystalline solid form A, which is obtained by atleast one of:

(i) crystallizing[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureapotassium salt from at least one solvent selected from the groupconsisting of ethanol, methanol, and combinations thereof and dryingsuch that the crystal contained some solvent; and(ii) heating[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureapotassium salt in at least one solvent selected from the groupconsisting of ethanol, methanol, and combinations thereof; crystallizingat a temperature of from about 50° C. to −10° C. and drying until thecrystals contained at least about 0.05% solvent.

In another embodiment of the present invention there is provided[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureapotassium salt in a crystalline solid form B, which is obtained by atleast one of:

(i) heating[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureapotassium salt in a solvent combination of ethanol and water;crystallizing at a temperature of from about 50° C. to −10° C. anddrying until the crystals contain less than 0.05% solvent; and(ii) crystallizing[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureapotassium salt from a solvent combination of ethanol and water anddrying such that the crystal contained less than 0.05% solvent.

In another embodiment of the present invention there is provided aamorphous crystalline form of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureapotassium salt by triturating in isopropanol and drying.

In another embodiment of the present invention there is provided aamorphous crystalline form of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureasodium salt which is obtained by at least one of:

(i) heating[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureasodium salt in at least one solvent selected from the group consistingof isopropanol, acetonitrile, ethanol and combinations thereof; andcrystallizing at a temperature of from about 50° C. to −10° C.;(ii) crystallizing[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureasodium salt from at least one solvent selected from the group consistingof isopropanol, acetonitrile, ethanol and combinations thereof; and(iii) heating[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureasodium salt in high humidity.

Furthermore, the present invention is directed to the above describedprocesses for the preparation of crystalline solid and amorphous formsof[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureapotassium and sodium salts.

[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureain a crystalline solid or amorphous form may be prepared by variousmethods as further described below in the Examples. The examplesillustrate, but do not limit the scope of the present invention.[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureain crystalline solid or amorphous forms may be isolated using typicalisolation and purification techniques known in the art, including, forexample, chromatographic, recrystallization and other crystallizationprocedures as well as modification of the procedures outlined above.

VI. Pharmaceutical Compositions

A compound of formula (I) according to the invention may be formulatedinto pharmaceutical compositions. Accordingly, the invention alsoprovides a pharmaceutical composition for preventing or treatingthrombosis in a mammal, particularly those pathological conditionsinvolving platelet aggregation, containing a therapeutically effectiveamount of a compound of formula (I) or a pharmaceutically acceptablesalt thereof, each as described above, and a pharmaceutically acceptablecarrier or agent. Preferably, a pharmaceutical composition of theinvention contains a compound of formula (I), or a salt thereof, in anamount effective to inhibit platelet aggregation, more preferably,ADP-dependent aggregation, in a mammal, in particular, a human.Pharmaceutically acceptable carriers or agents include those known inthe art and are described below.

Pharmaceutical compositions of the invention may be prepared by mixingthe compound of formula (I) with a physiologically acceptable carrier oragent. Pharmaceutical compositions of the invention may further includeexcipients, stabilizers, diluents and the like and may be provided insustained release or timed release formulations. Acceptable carriers,agents, excipients, stablilizers, diluents and the like for therapeuticuse are well known in the pharmaceutical field, and are described, forexample, in Remington's Pharmaceutical Sciences, Mack Publishing Co.,ed. A. R. Gennaro (1985). Such materials are nontoxic to the recipientsat the dosages and concentrations employed, and include buffers such asphosphate, citrate, acetate and other organic acid salts, antioxidantssuch as ascorbic acid, low molecular weight (less than about tenresidues) peptides such as polyarginine, proteins, such as serumalbumin, gelatin, or immunoglobulins, hydrophilic polymers such aspolyvinylpyrrolidinone, amino acids such as glycine, glutamic acid,aspartic acid, or arginine, monosaccharides, disaccharides, and othercarbohydrates including cellulose or its derivatives, glucose, mannoseor dextrins, chelating agents such as EDTA, sugar alcohols such asmannitol or sorbitol, counterions such as sodium and/or nonionicsurfactants such as TWEEN, or polyethyleneglycol.

Further embodiments of the invention include pharmaceutical compositionsof[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea,its salts and forms, including in therapeutically effective amounts ofForm A, Form B, and the amorphous form. Said amounts of the at least oneof said forms may or may not be in therapeutically effective amounts.Such pharmaceutical compositions may be in the form of a solid oralcomposition such as a tablet or a capsule or as a dry powder forinhalation.

VII. Methods of Treatment/Administration

A. Preventing and Treating Disease Conditions Characterized by UndesiredThrombosis

Methods for preventing or treating thrombosis in a mammal embraced bythe invention administering a therapeutically effective amount of acompound of formula (I) alone or as part of a pharmaceutical compositionof the invention as described above to a mammal, in particular, a human.Compounds of formula (I) and pharmaceutical compositions of theinvention containing a compound of formula (I) of the invention aresuitable for use alone or as part of a multi-component treatment regimenfor the prevention or treatment of cardiovascular diseases, particularlythose related to thrombosis. For example, a compound or pharmaceuticalcomposition of the invention may be used as a drug or therapeutic agentfor any thrombosis, particularly a platelet-dependent thromboticindication, including, but not limited to, acute myocardial infarction,unstable angina, chronic stable angina, transient ischemic attacks,strokes, peripheral vascular disease, preeclampsia/eclampsia, deepvenous thrombosis, embolism, disseminated intravascular coagulation andthrombotic cytopenic purpura, thrombotic and restenotic complicationsfollowing invasive procedures, e.g., angioplasty, carotidendarterectomy, post CABG (coronary artery bypass graft) surgery,vascular graft surgery, stent placements and insertion of endovasculardevices and protheses, and hypercoagulable states related to geneticpredisposition or cancers. In other groups of embodiments, theindication is selected from the group consisting of percutaneouscoronary intervention (PCI) including angioplasty and/or stent, acutemyocardial infarction (AMI), unstable angina (USA), coronary arterydisease (CAD), transient ischemic attacks (TIA), stroke, peripheralvascular disease (PVD), Surgeries-coronary bypass, carotid endarectomy

Compounds and pharmaceutical compositions of the invention may also beused as part of a multi-component treatment regimen in combination withother therapeutic or diagnostic agents in the prevention or treatment ofthrombosis in a mammal. In certain preferred embodiments, compounds orpharmaceutical compositions of the invention may be coadministered alongwith other compounds typically prescribed for these conditions accordingto generally accepted medical practice such as anticoagulant agents,thrombolytic agents, or other antithrombotics, including plateletaggregation inhibitors, tissue plasminogen activators, urokinase,prourokinase, streptokinase, heparin, aspirin, or warfarin oranti-inflammatories (non-steriodal anti-inflammatories, cyclooxygenaseII inhibitors).

Coadministration may also allow for application of reduced doses of boththe anti-platelet and the thrombolytic agents and therefore minimizepotential hemorrhagic side-effects. Compounds and pharmaceuticalcompositions of the invention may also act in a synergistic fashion toprevent reocclusion following a successful thrombolytic therapy and/orreduce the time to reperfusion.

The compounds and pharmaceutical compositions of the invention may beutilized in vivo, ordinarily in mammals such as primates, (e.g.,humans), sheep, horses, cattle, pigs, dogs, cats, rats and mice, or invitro. The biological properties, as defined above, of a compound or apharmaceutical composition of the invention can be readily characterizedby methods that are well known in the art such as, for example, by invivo studies to evaluate antithrombotic efficacy, and effects onhemostasis and hematological parameters.

Compounds and pharmaceutical compositions of the invention may be in theform of solutions or suspensions. In the management of thromboticdisorders the compounds or pharmaceutical compositions of the inventionmay also be in such forms as, for example, tablets, capsules or elixirsfor oral administration, suppositories, sterile solutions or suspensionsor injectable administration, and the like, or incorporated into shapedarticles. Subjects (typically mammalian) in need of treatment using thecompounds or pharmaceutical compositions of the invention may beadministered dosages that will provide optimal efficacy. The dose andmethod of administration will vary from subject to subject and bedependent upon such factors as the type of mammal being treated, itssex, weight, diet, concurrent medication, overall clinical condition,the particular compound of formula (I) employed, the specific use forwhich the compound or pharmaceutical composition is employed, and otherfactors which those skilled in the medical arts will recognize.

B. Therapeutically Effective Amount

Dosage formulations of compounds of formula (I), or pharmaceuticalcompositions contain a compound of the invention, to be used fortherapeutic administration must be sterile. Sterility is readilyaccomplished by filtration through sterile membranes such as 0.2 micronmembranes, or by other conventional methods. Formulations typically willbe stored in a solid form, preferably in a lyophilized form. While thepreferred route of administration is orally, the dosage formulations ofcompounds of formula (I) or pharmaceutical compositions of the inventionmay also be administered by injection, intravenously (bolus and/orinfusion), subcutaneously, intramuscularly, colonically, rectally,nasally, transdermally or intraperitoneally. A variety of dosage formsmay be employed as well including, but not limited to, suppositories,implanted pellets or small cylinders, aerosols, oral dosage formulationsand topical formulations such as ointments, drops and dermal patches.The compounds of formula (I) and pharmaceutical compositions of theinvention may also be incorporated into shapes and articles such asimplants which may employ inert materials such biodegradable polymers orsynthetic silicones as, for example, SILASTIC, silicone rubber or otherpolymers commercially available. The compounds and pharmaceuticalcompositions of the invention may also be administered in the form ofliposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles and multilamellar vesicles. Liposomes can be formedfrom a variety of lipids, such as cholesterol, stearylamine orphosphatidylcholines.

Therapeutically effective dosages may be determined by either in vitroor in vivo methods. For each particular compound or pharmaceuticalcomposition of the present invention, individual determinations may bemade to determine the optimal dosage required. The range oftherapeutically effective dosages will be influenced by the route ofadministration, the therapeutic objectives and the condition of thepatient. For injection by hypodermic needle, it may be assumed thedosage is delivered into the body's fluids. For other routes ofadministration, the absorption efficiency must be individuallydetermined for each compound by methods well known in pharmacology.Accordingly, it may be necessary for the therapist to titer the dosageand modify the route of administration as required to obtain the optimaltherapeutic effect. The determination of effective dosage levels, thatis, the dosage levels necessary to achieve the desired result, will bereadily determined by one skilled in the art. Typically, applications ofcompound are commenced at lower dosage levels, with dosage levels beingincreased until the desired effect is achieved.

The determination of effective dosage levels, that is, the dosage levelsnecessary to achieve the desired result, i.e., platelet ADP receptorinhibition, will be readily determined by one skilled in the art.Typically, applications of a compound or pharmaceutical composition ofthe invention are commenced at lower dosage levels, with dosage levelsbeing increased until the desired effect is achieved. The compounds andcompositions of the invention may be administered orally in an effectiveamount within the dosage range of about 0.01 to 1000 mg/kg in a regimenof single or several divided daily doses. If a pharmaceuticallyacceptable carrier is used in a pharmaceutical composition of theinvention, typically, about 5 to 500 mg of a compound of formula (I) iscompounded with a pharmaceutically acceptable carrier as called for byaccepted pharmaceutical practice including, but not limited to, aphysiologically acceptable vehicle, carrier, excipient, binder,preservative, stabilizer, dye, flavor, etc. The amount of activeingredient in these compositions is such that a suitable dosage in therange indicated is obtained.

C. Administration

Therapeutic compound liquid formulations generally are placed into acontainer having a sterile access port, for example, an intravenoussolution bag or vial having a stopper pierceable by hypodermic injectionneedle.

Typical adjuvants which may be incorporated into tablets, capsules,lozenges and the like are binders such as acacia, corn starch orgelatin, and excipients such as microcrystalline cellulose,disintegrating agents like corn starch or alginic acid, lubricants suchas magnesium stearate, sweetening agents such as sucrose or lactose, orflavoring agents. When a dosage form is a capsule, in addition to theabove materials it may also contain liquid carriers such as water,saline, or a fatty oil. Other materials of various types may be used ascoatings or as modifiers of the physical form of the dosage unit.Sterile compositions for injection can be formulated according toconventional pharmaceutical practice. For example, dissolution orsuspension of the active compound in a vehicle such as an oil or asynthetic fatty vehicle like ethyl oleate, or into a liposome may bedesired. Buffers, preservatives, antioxidants and the like can beincorporated according to accepted pharmaceutical practice.

D. Combination Therapies

The compounds of the present invention may also be used in combinationwith other therapeutic or diagnostic agents. In certain preferredembodiments, the compounds of this invention may be coadministered alongwith other compounds typically prescribed for these conditions accordingto generally accepted medical practice such as anticoagulant agents,thrombolytic agents, or other antithrombotics, including plateletaggregation inhibitors, tissue plasminogen activators, urokinase,prourokinase, streptokinase, heparin, aspirin, or warfarin. Thecompounds of the present invention may act in a synergistic fashion toprevent reocclusion following a successful thrombolytic therapy and/orreduce the time to reperfusion. These compounds may also allow forreduced doses of the thrombolytic agents to be used and thereforeminimize potential hemorrhagic side-effects. The compounds of thisinvention can be utilized in vivo, ordinarily in mammals such asprimates, (e.g. humans), sheep, horses, cattle, pigs, dogs, cats, ratsand mice, or in vitro.

It should be understood that the foregoing discussion, embodiments andexamples merely present a detailed description of certain preferredembodiments. It will be apparent to those of ordinary skill in the artthat various modifications and equivalents can be made without departingfrom the spirit and scope of the invention. All the patents, journalarticles and other documents discussed or cited above are hereinincorporated by reference.

The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof.

VIII. Examples General Methods

The starting materials and reagents used in preparing these compoundsgenerally are either available from commercial suppliers, such asAldrich Chemical Co., or are prepared by methods known to those skilledin the art following procedures set forth in references such as Fieserand Fieser's Reagents for Organic Synthesis, Wiley & Sons: New York,1967-2004, Volumes 1-22; Rodd's Chemistry of Carbon Compounds, ElsevierScience Publishers, 1989, Volumes 1-5 and Supplementals; and OrganicReactions, Wiley & Sons: New York, 2005, Volumes 1-65. The followingsynthetic reaction schemes are merely illustrative of some methods bywhich the compounds of the present invention can be synthesized, andvarious modifications to these synthetic reaction schemes can be madeand will be suggested to one skilled in the art having referred to thedisclosure contained in this Application.

The starting materials and the intermediates of the synthetic reactionschemes can be isolated and purified if desired using conventionaltechniques, including but not limited to, filtration, distillation,crystallization, chromatography, and the like. Such materials can becharacterized using conventional means, including physical constants andspectral data.

Unless specified to the contrary, the reactions described hereinpreferably are conducted under an inert atmosphere at atmosphericpressure at a reaction temperature range of from about −78° C. to about150° C., more preferably from about 0° C. to about 125° C., and mostpreferably and conveniently at about room (or ambient) temperature,e.g., about 20° C. to about 75° C.

Referring to the examples that follow, compounds of the presentinvention were synthesized using the methods described herein, or othermethods, which are well known in the art.

The compounds and/or intermediates were characterized by highperformance liquid chromatography (HPLC) using a Waters Alliancechromatography system with a 2695 Separation Module (Milford, Mass.).The analytical columns were C-18 SpeedROD RP-18E Columns from Merck KGaA(Darmstadt, Germany). Alternately, characterization was performed usinga Waters Unity (HPLC) system with Waters Acquity HPLC BEH C-18 2.1 mm×15mm columns. A gradient elution was used, typically starting with 5%acetonitrile/95% water and progressing to 95% acetonitrile over a periodof 5 minutes for the Alliance system and 1 minute for the Acquitysystem. All solvents contained 0.1% trifluoroacetic acid (TFA).Compounds were detected by ultraviolet light (UV) absorption at either220 or 254 nm. HPLC solvents were from EMD Chemicals, Inc. (Gibbstown,N.J.). In some instances, purity was assessed by thin layerchromatography (TLC) using glass backed silica gel plates, such as, forexample, EMD Silica Gel 60 2.5 cm×7.5 cm plates. TLC results werereadily detected visually under ultraviolet light, or by employing wellknown iodine vapor and other various staining techniques.

Mass spectrometric analysis was performed on one of two Agilent 1100series LCMS instruments with acetonitrile/water as the mobile phase. Onesystem using TFA as the modifier and measures in positive ion mode[reported as MH⁺, (M+1) or (M+H)⁺] and the other uses either formic acidor ammonium acetate and measures in both positive [reported as MH⁺,(M+1) or (M+H)⁺] and negative [reported as M−, (M−1) or (M−H)⁻] ionmodes.

Nuclear magnetic resonance (NMR) analysis was performed on some of thecompounds with a Varian 400 MHz NMR (Palo Alto, Calif.). The spectralreference was either TMS or the known chemical shift of the solvent.

The purity of some of the invention compounds is assessed by elementalanalysis (Robertson Microlit, Madison N.J.).

Melting points are determined on a Laboratory Devices MeI-Temp apparatus(Holliston, Mass.).

Preparative separations were carried out using either an Sq16x or anSg100c chromatography system and prepackaged silica gel columns allpurchased from Teledyne Isco, (Lincoln, Nebr.). Alternately, compoundsand intermediates were purified by flash column chromatography usingsilica gel (230-400 mesh) packing material, or by HPLC using a C-18reversed phase column. Typical solvents employed for the Isco systemsand flash column chromatography were dichloromethane, methanol, ethylacetate, hexane, acetone, aqueous hydroxyamine and triethyl amine.Typical solvents employed for the reverse phase HPLC were varyingconcentrations of acetonitrile and water with 0.1% trifluoroacetic acid.

Instrumental for Solid Forms 1. FT Infrared Spectroscopy (FTIR)

Samples were studied on a Perkin-Elmer Spectrum One fitted with aUniversal ATR sampling accessory and running Spectrum V5.0.1 software.The resolution was set to 4 cm⁻¹ and 16 scans were collected over therange 4000 cm⁻¹ to 400 cm⁻¹. Control and Analysis software: Spectrum v5.0.1.

2. Differential Scanning Calorimetry (DSC)

DSC data (thermograms) were collected on a TA instruments Q1000 equippedwith a 50 position auto-sampler. The energy and temperature calibrationstandard was indium. Samples were heated at a rate of 10° C./min from10° C. to 250° C. A nitrogen purge at 30 ml/min was maintained over thesample.

Between 1 and 3 mg of sample was used, unless otherwise stated, and allsamples were sealed in an aluminum pan with a pinhole in the lid.Control software: Advantage for Q series v 2.2.0.248, Thermal AdvantageRelease 4.2.1. Analysis software: Universal Analysis 2000 v 4.1D Build4.1.0.16

3. Thermogravimetric Analysis (TGA)

TGA data (thermograms) were collected on a TA Instrument Q500 TGA with a16 position auto-sampler. Samples were heated at a rate of 10°C./minute. A nitrogen purge of 100 ml/min was maintained over thesample.

Typically 5-20 mg of sample was loaded onto a tared open aluminum openpan. Control software: Advantage for Q series v 2.2.0.248, ThermalAdvantage Release 4.2.1. Analysis software: Universal Analysis 2000 v4.1D Build 4.1.0.16

4. XRPD (X-Ray Powder Diffraction) Bruker AXS C2 GADDS Diffractometer

X-ray powder diffraction patterns for the samples were acquired on aBruker AXS C2 GADDS diffractometer using Cu Kα radiation (40 kV, 40 mA),automated XYZ stage, laser video microscope for auto-sample positioningand a HiStar 2-dimensional area detector. X-ray optics consists of asingle Gobel multilayer mirror coupled with a pinhole collimator of 0.3mm.

Beam divergence, i.e. the effective size of the X-ray beam on thesample, was approximately 4 mm. A θ-θ continuous scan mode was employedwith a sample to detector distance of 20 cm which gives an effective 20range of 3.2°-29.8°. A typical exposure time of a sample was 120 s.

Samples run under ambient conditions were prepared as flat platespecimens using powder as received without grinding. Approximately 1-2mg of the sample was lightly pressed on a glass slide to obtain a flatsurface. Control software: GADDS for WNT v 4.1.16. Analysis software:Diffrac Plus Release 3 EVA v 9.0.0.2

5. Gravimetric Vapor Sorption (GVS) Studies

Isotherms were collected on a Hiden IGASorp moisture sorption analyzerrunning CFRSorp software. Sample sizes were typically ca. 10 mg. Amoisture adsorption/desorption isotherm was performed as outlined below.The samples were loaded and unloaded at room humidity and temperature(ca. 40% RH, 25° C.). The standard isotherm run was a single cyclestarting at 40% RH. The humidity was stepped as follows: 40, 50, 60, 70,80, 90, 85, 75, 65, 55, 45, 35, 25, 15, 5, 0, 10, 20, 30, 40. Controland Analysis software: IGASorp Controller v 1.10, IGASorp SystemsSoftware v 3.00.23.

6. ¹H NMR

Spectra were collected on a Bruker 400 MHz equipped with auto sampler.Samples were prepared in d₆-DMSO.

7. Purity Analysis

Purity analysis was performed on an Agilent HP1100 system equipped witha diode array detector.

Method: Gradient

Column details: Betabasic C18, 5 μm, 150×4.6 mm

Column Temperature: 25° C.

Injection volume: 5 μlFlow Rate ml/min: 0.8 ml/minDetection wavelength: 325 nmPhase A: 0.1% v/v aqueous formic acidPhase B: Acetonitrile:water 90:10 with 0.1% v/v formic acid

TABLE 3 Mobile phase timetable. Time/Min % A % B 0 90 10 2 90 10 17 1090 21 10 90 21.3 90 10 25 90 10

TABLE 4 potassium salt sodium salt Purity 99.4% (a/a) 99.4% (a/a)Impurities Individual peaks ≧0.1% (a/a) % (a/a) % (a/a) RRT = 0.57 0.140.11 RRT = 1.08 0.15 0.18 Total of peaks <0.1% (a/a) 0.3 0.3

Example 1 Synthesis of the Intermediate Sulfonylurea Carbamate (8)

Step 1 Preparation 5-chlorothiophene-2-sulfonyl chloride

The following procedure was adapted from C. A. Hunt, et al. J. Med.Chem. 1994, 37, 240-247. In a three-necked R.B. flask, equipped with amechanical stirrer, an air condenser, a dropping funnel, and amoisture-guard tube, was placed chlorosulfonic acid (240 mL, 3.594 mol).Under stirring, PCl₅ (300 g, 1.44 mol, 0.40 equiv) was added inportions, over ca. 45 mins. During the addition, a large volume of HClgas evolved vigorously, but the temperature of the mixture did not risesignificantly (<40° C.). By the time all the PCl₅ had been added, analmost clear, pale yellow solution resulted, with only a few solidpieces of PCl₅ floating in the suspension. It was stirred until gasevolution ceased (0.5 h).

Then the reaction vessel was cooled in ice, and 2-chloro-thiophene (66.0mL, 0.715 mol) was added via the dropping funnel, over 1.0 h. With theaddition of the very first few drops of 2-Cl-thiophene, the mixtureturned dark purple, and by the time all of the thiophene had been added,a dark purple solution resulted. During the addition, HCl gas evolvedcontinuously, at a slow rate. The reaction mixture was then stirred atroom temperature overnight.

Then the mixture, dark-purple clear solution, was added dropwise tocrushed ice (3 L), over 0.5 h. On addition to ice, the purple colordisappeared instantaneously; the colorless thin emulsion was stirredmechanically at room temperature for ca. 15 h. Then the mixture wasextracted with CH₂Cl₂ (3×300 mL). The combined CH₂Cl₂-extract was washedwith water (1×200 mL), saturated NaHCO₃ (1×250 mL), brine (1×100 mL),dried (Na₂SO₄), and concentrated on a rotary evaporator to yield thecrude product as a pale yellow glue, which showed a tendency tosolidify, yielding a semi-solid mass. This was then purified byhigh-vacuum distillation (bp 110-112°/12 mm) to yield 135.20 g (88%) ofthe title compound as a colorless/pale-yellow semi solid.

Step 2 5-chlorothiophene-2-sulfonamide

The following procedure was adapted from C. A. Hunt, et al. J. Med.Chem. 1994, 37, 240-247. In a three-necked R. B. flask, equipped with amechanical stirrer, conc. NH₄OH (500 mL, 148.50 g NH₃, 8.735 mol NH₃,13.07 equiv NH₃) was placed. The flask was cooled in ice and5-chlorothiophene-2-sulfonyl chloride (145.0 g, 0.668 mol) was added, inportions over 0.5 h (it is a low-melting solid, and it was melted bywarming, which was then conveniently added via a wide-bored polyethylenepipette). The sulfonyl chloride immediately solidifies in the reactionflask. After all the sulfonyl chloride had been added, the flaskcontaining it was rinsed with THF (25 mL), and this also was transferredto the reaction vessel. Then the heavy suspension was stirred at roomtemperature for ca. 20 h. At the end of this time the reaction mixturewas still a suspension but of a different texture.

Then the mixture was cooled in ice, diluted with H₂O (1.5 l), andacidified with conc. HCl to pH ca. 3. The solid product was collected byfiltration using a Buchner funnel, rinsed with cold water, and air-driedto afford the title compound as a colorless solid, 103.0 g (78%). MS(M−H): 196.0; 198.0

Step 3 Ethyl 5-chlorothiophen-2-ylsulfonylcarbamate

A 2-L 3-necked R.B. flask, equipped with a mechanical stirrer and adropping flunnel, was charged with sulfonamide (60.0 g, 303.79 mmol),and Cs₂CO₃ (200 g, 613.83 mmol, 2.02 equiv) in THF (900 mL). The clearsolution was cooled in ice, and ethyl chloroformate (70.0 mL, 734.70mmol, 2.418 equiv) was added over ca. 30 mins. The heavy suspension wasthen stirred at room temperature for ca. 36 h.

Then the mixture was diluted with water (200 mL) to yield a clearcolorless solution, which was concentrated on rotary evaporator toone-third its volume. This was then diluted with EtOAc (250 mL), cooledin ice, and acidified with 6N HCl to pH ca. 1. The biphasic mixture wastransferred to a separatory funnel, layers were separated, and theaqueous layer was again extracted with 2×75 mL EtOAc. The combinedorganic extract was washed with water/brine (2×50 mL), brine (1×50 mL),dried over Na₂SO₄, and concentrated to yield the title compound aslightly colored oil. This was purified by filtration through asilica-gel plug. The crude product was applied to the silica-gel plug ona sintered funnel in EtOAc, and then was eluted with EtOAc (1 liter).Concentration of the EtOAc filtrate provided the title compound 8 as acolorless solid, 71.28 g (87%). MS (M−H): 268.0; 270.0. ¹H NMR (DMSO): δ7.62 (d, 1H), 7.25 (d, 1H), 4.10 (q, 2H), 1.16 (t, 3H).

Example 2 Synthesis of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea(7a)

Step 1

Aniline 1 (¹H NMR (DMSO): δ 7.58 (dd, 1H), 6.72 (dd, 1H), 3.77 (s, 3H);6.0 g, 32.085 mmol) was placed in a 500 mL round bottomed flask and 20%phosgene in toluene (175 mL, 332.50 mmol, 10.36 equiv) was added. Theresulting somewhat sticky suspension was then magnetically stirredovernight at room temperature resulting in a clear, colorless solution.An aliquot removed, blown dry with argon, quenched with MeOH, andanalyzed by RP-HPLC/MS to show no unreacted aniline 1 and cleanformation of the isocyanate 2a and/or carbamoyl chloride 2b as analyzedas its methyl-carbamate. The mixture was concentrated first by rotaryevaporation and then under high vacuum to yield 6.76 g (99% yield) ofthe isocyanate 2a and/or carbamoyl chloride 2b as a free-flowingcolorless solid.

Step 2

In a 500 mL R. B. flask was placed N-Boc-1,4-phenylenediamine (6.22 g,29.866 mmol, 1.20 equiv) in DMF (100 mL). Triethylamine (5.30 mL, 38.025mmol, 1.52 equiv) was syringed in. Then the clear, dark-brown solutionwas treated with a solution of the isocyanate 2a (5.30 g, 24.88 mmol)and/or carbamoyl chloride 2b in DMF (50 mL), dropwise, over 15 minutes.After the addition was over, a slightly turbid mixture resulted, whichwas stirred overnight at room-temperature. An aliquot was analyzed,after quenching with MeOH, to show no unreacted isocyanate, and cleanformation of the urea, 3a, and quinazoline-1,3-dione, 4a, in a ratio ofca. 2.5:1. MS (M−H): 388.0.

DBU (3.75 mL, 25.07 mmol, ca. 1.0 equiv) was then syringed in, dropwise,over 5 minutes, resulting in a clear dark-brown solution. This wasstirred at room temperature for 3.0 h resulting in a turbid mixture.HPLC analysis showed no urea 3a and clean formation of thequinazoline-1,3-dione 4a. The reaction mixture was concentrated on arotary evaporator to yield the crude product as a solid. This was driedunder high vacuum, and then triturated with CH₂Cl₂/H₂O (5:1) to yield8.40 g of 4a as an almost colorless solid (87% yield). ¹H NMR (DMSO): δ9.39 (s, 1H), 7.68 (dd, 1H), 7.45 (d, 2H), 7.03 (m, 2H), 6.98 (dd, 1H),1.48 (s, 9H).

Step 3

The N-Boc-aniline 4a (4.0 g, 10.28 mmol) was placed in a round-bottomed.flask and 4N HCl in dioxane (50.0 mL, 200 mmol, 19.40 equiv) was added.The heavy, negligibly solvated suspension was stirred at roomtemperature for 5.0 h. HPLC showed no starting material and cleanformation of the aniline 5a. The mixture was then concentrated on arotary evaporator to yield the crude product. The solid thus obtainedwas triturated with CH₂Cl₂ to yield 3.22 g of pure 5a as an almostcolorless solid (96% yield). MS (M−H): 290.3. ¹H NMR (DMSO): δ 11.75 (s,1H), 7.88 (dd, 1H), 7.32 (m, 4H), 7.21 (dd, 1H).

Step 4

The difluoro-compound, 5a (1.0 g, 3.072 mmol) was placed in a screw-capsealed tube. DMSO (20 mL) was added, followed by methylamine (2.0M inTHF) (15.0 mL, 30 mmol, 9.76 equiv), resulting in a clear solution. Thiswas then heated in an oil bath to 110° C. for 3 h. HPLC showed nounreacted 5a and clean formation of 5b. The mixture was then cooled toroom temperature, all the MeNH₂ and THF were evaporated, and the residuewas diluted with 100 mL water to precipitate 5b. After stirring for ca.2 h at room temperature, the colorless solid was collected by filtrationthrough a Buchner funnel and rinsed with H₂O (100 mL), and air-dried.HPLC analysis of this solid showed it to be pure and devoid of any DBU.This solid was further purified by triturating with Et₂O, and thenCH₂Cl₂ as in the previous route to this aniline to give 875 mg of thetitle compound (95% yield). MS (M+1) 301.2. ¹H NMR (DMSO): δ 11.10 (s,1H), 7.36 (d, 1H), 6.78 (d, 2H), 6.75 (m, 1H), 6.56 (d, 2H), 6.20 (d,1H), 5.18 (d, 2H), 2.76 (d, 3H).

Step 5 Synthesis of1-(5-chlorothiophen-2-ylsulfonyl)-3-(4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)urea(7a)

The reaction mixture comprising of the aniline (16.0 g, 53.33 mmol) andethyl-sulfonyl-carbamate (28.77 g, 106.66 mmol, 2.0 equiv) in CH₃CN(1300 mL) was heated to reflux for 36 h. During this time, the reactionmixture remained as a heavy suspension. HPLC analysis showed a cleanreaction, and <1% unreacted anilne. The heavy suspension was cooled toroom temperature and filtered through a Buchner funnel. The colorlesssolid product was further rinsed with CH₃CN (3×40 mL). HPLC of thefiltrate showed the presence of only a trace amount of the desiredproduct, most of it being the excess carbamate. The crude product wasthen triturated with CH₂Cl₂ (400 mL), and the almost colorless solidproduct was collected by filtration through a Buchner funnel: Yield,25.69 g (92%). MS (M+1): 524.0; 526.0. ¹H NMR (DMSO):

δ 11.20 (s, 1H), 9.15 (s, 1H), 7.68 (d, 1H), 7.42 (d, 2H), 7.36 (d, 1H),7.26 (m, 1H), 7.16 (d, 2H), 6.78 (m, 1H), 6.24 (d, 1H), 2.78 (d, 3H).

Example 3[4-(6-chloro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea(6b)

The compound in Example 3 is synthesized as described for Example 2(Step 1-5) except starting with methyl-2-amino-5-chloro-4-fluorobenzoatewhich was synthesized by reduction ofmethyl-2-nitro-5-chloro-4-fluorobenzoate with Pt(S)C.

Example 4 Synthesis of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylurea(6a) and salt (7a)

Step 1

Methyl 2-amino-4,5-difluorobenzoate [2] (38 Kg, 1.0 eq) anddichloromethane (560 Kg, 8×, ACS >99.5%) were charged to a PP1-R1000reactor (2000L GL reactor). The reaction mixture was agitated for 5mins. 4-Nitrophenylchloroformate (49.1 Kg, 1.2 equiv) was charged intoPP1-R2000 reactor (200L) followed by dichloromethane (185 Kg) andagitated the contents for 5 mins. After pressurizing the 200L reactorthe 4-nitrophenylchloroformate solution was transferred into the 2000Lreactor containing dichloromethane solution of [2]. The reaction mixturewas heated to 40±5° C. (reflux) under nitrogen gas purge for 3 hrs. Therepresentative TLC analysis confirmed reaction completion (in-processTLC, no compound 2 remaining; 99:1 CHCl₃-MeOH). The solution was cooledto 30° C. and distilled off 460 Kg of dichloromethane under vacuum. The2000L reactor was charged with 520 Kg of hexanes and cooled the contentsof the reactor to 0±5° C. and agitated for 4 hrs. The solid obtained wasfiltered through GF Nutsche filter lined with a sheet of T-515 LF Typarfilter and a sheet of MeI-Tuf 1149-12 filter paper. The filter cake waswashed with 20 Kg of hexanes and vacuum dried at 35° C. until constantweight attained. The dry product was discharged (70.15 Kg) with 98%yield. The product confirmed by ¹H NMR and TLC analysis.

Step 2 Synthesis of3-(4-aminophenyl)-6,7-difluoroquinazoline-2,4(1H,3H)-dionehydrochloride, compound 5b

The PP1-R1000 (2000L GL reactor) reactor was charged with 3a (64.4 Kg,1.0 eq), anhydrous tetrahydrofuran (557 Kg) and triethylamine (2.2 Kg,0.1 equiv). The charging line of 2000L GL reactor was rinsed withtetrahydrofuran (10 Kg). The contents of the reactor were agitated for25 mins. during that period complete solution was obtained. ThePP1-R2000 (200L HP reactor) reactor was charged withN-Boc-p-phenylenediamine (38 Kg, 1.0 equiv), tetrahydrofuran (89 Kg) andagitated for 30 mins. until complete solution obtained. The contents ofthe 200L HP reactor were transferred to the 2000L GL reactor containingthe compound 3a and then heated at 65±5° C. for 2 hrs. The reaction wasdeemed complete monitored by HPLC after confirming the disappearance ofstarting material 3a (in-process specification <1%). The contents of2000L GL reactor were cooled to 20±5° C. and then charged with sodiummethoxide (25% solution in methanol, 41.5 Kg, 1.05 equiv.) over 20 mins.maintaining the temperature below 30° C. The charging lines were rinsedwith tetrahydrofuran (10 Kg). The contents were agitated at 25±5° C. for4 hrs. In-process HPLC analysis confirmed the completion of the reactionwhen the amount of compound 3b remaining in the reaction mixture is <1%.To this reaction mixture added filtered process water (500 Kg) anddistilled under vacuum the 2000L GL reactor contents into clean 200L GLreceiver until 300 Kg of solvent is distilled. The solids obtained werefiltered using GL Nutsche filter and washed with process filtered wateruntil the color of the solid the compound 4b is white to grayish. The2000L GL reactor is charged with wet compound 4b filter cake, dioxane(340 Kg) and agitated the contents for 1 hr. The filterable solidobtained were filtered through GL Nutsche filter with a sheet of T-515LF Typar filter paper. The solid cake was blow dried for 2 hrs and thencharged with dioxane (200 Kg) into the 2000L GL reactor. The contentswere agitated for 10 min. and then charged with 4 N HCl in dioxane (914Kg) over 3 hrs and maintaining the internal temperature below 30° C. Thecharging line was rinsed with additional dioxane (10 Kg) and thecontents of the reactor were agitated for 6 hrs at 25±5° C. Thecompletion of the reaction is monitored by HPLC (in process controlcompound 4 is <1% in the reaction mixture) for the conversion ofcompound 4b to compound 5b. The contents of the reactor were cooled to5+5° C. for 2 hr and the solid obtained was filtered through GL Nutschefilter followed by washing with dioxane (50 Kg). The filter cake wasblow dried with 8±7 psig of nitrogen for 30 mins. and purity analyzed byHPLC. The filtered solid was dried to constant weight in vacuum oven at45° C. for 48 hr. The compound 5b (65.8 Kg, actual yield 110.6%) wasdischarged and analyzed by ¹HNMR and HPLC analysis. ¹H NMR (DMSO): δ11.75 (s, 1H), 7.88 (dd, 1H), 7.32 (m, 4H), 7.21 (dd, 1H).

Step 3 Synthesis of3-(4-aminophenyl)-6-fluoro-7-(methylamino)quinazoline-2,4(1H,3H)-dione,Compound 5c

The PP1-R2000 (200 L HP reactor) was charged with compound 5b (18 Kg,1.0 eq.) and pressurized with 100±5 psig of nitrogen. Vent the nitrogenfrom the reactor through the atmospheric vent line then open thecondenser valve and then charged dimethyl sulfoxide into the reactor(>99.7%, 105 Kg) under blanket of argon. The reactor contents wereagitated at 22° C. (19-25° C.) for 15 mins. and then pulled maximumachievable vacuum on the 200L HP reactor and close all the valves. Usingthe established vacuum charged to the 200L HP reactor methylamine (33%wt % in absolute ethanol, 37.2 Kg) at a rate that maintains the internaltemperature at 25±5° C. and kept a nitrogen blanket on the reagentsolution during charging. After rinsing the charging line with dimethylsulfoxide (5 Kg) closed the 200L HP reactor condenser valve and heatedthe reactor contents to 110±5° C. The contents of the reactor wereagitated for at least 5 hrs. at 110±5° C. In-process HPLC taken after 5hr 40 mins. showed compound 5b content of 0.09%, indicating completionof the reaction (in-process specification ≦1%). The contents of 200L HPreactor were cooled to 25±5° C. While the 200L reactor is cooling,closed all the valves of the PP1-R1000 reactor (2000L GL reactor) andcharged with process filtered water (550 Kg). The contents of the 200LHP reactor were transferred to the 2000L GL reactor over 15 minutesfollowed by rinsing the charging line with process filtered water (50Kg). The contents of the 2000L GL reactor were agitated for 2 hrs at5±5° C. The filterable solids obtained were filtered onto PPF200 (GLnutsche filter) fitted with MeI-Tuf 1149-12 filter paper under vacuum.The wet filter cake was discharged and transferred into pre-lined vacuumtrays with Dupont's fluorocarbon film (Kind 100A). Clamped down thespecial oven paper (KAVON 992) over the vacuum trays containing the wetcompound 6 and transferred to the vacuum oven tray dryer. The oventemperature was set to 55° C. and compound 6 dried to a constant weightfor 12 hrs. The product 5c was discharged (12.70 Kg) in 76.5% yield(expected 85-95%). HPLC shows 98.96% purity and ¹H NMR confirmed thestructure for compound 5c. ¹H NMR (DMSO): δ 11.10 (s, 1H), 7.36 (d, 1H),6.78 (d, 2H), 6.75 (m, 1H), 6.56 (d, 2H), 6.20 (d, 1H), 5.18 (d, 2H),2.76 (d, 3H).

Step 45-Chloro-N-(4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenylcarbamoyl)thiophene-2-sulfonamide

The PP1-R2000 (200L HP reactor) reactor was charged with 6 (20.7 Kg, 1.0equiv), Ethyl 5-chlorothiophene-2-ylsulfonylcarbamate (37.5 Kg, 2.0equiv, >95%), dimethyl sulfoxide (>99%, 75 Kg) and agitated for 15 mins.While pulling maximum achievable vacuum, heated the 200L HP reactorNumber PP1-R2000 at 65±5° C. for 15 hrs. Took the representative samplefrom the reactor for HPLC analysis, in-process HPLC indicated <0.9%compound 5c remaining in the reaction mixture (in-process criteria forreaction completion compound 6<1%). Charged the 800L reactor numberPP5-R1000 with process filtered water (650 Kg) and then transferred the200L HP contents to the 800 L while maintaining the internal temperaturebelow 25° C. The Rinsed the 200L HP reactor with dimethyl sulfoxide (15Kg) and transfer to the 800L reactor which was then agitated for 2 hrsat 5±5° C. The solid formed was filtered through filter PP-F2000 to a200L GL receiver under vacuum and rinsed the filter cake with processfiltered water (60 Kg). Took a representative sample of the wet cake anddid HPLC analysis, if the purity of compound 6a is <95% (in-processcontrol <95% the dichloromethane trituration need). The 800L GL reactorwas charged with all the wet compound 6a, dichloromethane (315 Kg) andagitated the contents for 3 hrs. The solid was filtered through GLnutsche filter lined with 1 sheet of T515 LF TYPAR filter under vacuum.The filter cake was washed with dichloromethane (50 Kg) and blow driedthe cake with 8±7 psig of nitrogen for 15 mins. Transferred the filtercake into pre-lined vacuum trays with Dupont fluorocarbon film (Kind100A) and then into the vacuum oven tray dryer set at 60° C. for 12 hrs.The dried compound 6a was isolated (33.6 Kg, 93% yield) with HPLC purityof 93.5% and 4.3% of sulfonamide. ¹H NMR confirmed the structure forcompound 7. ¹HNMR (DMSO): δ 11.20 (s, 1H), 9.15 (s, 1H), 7.68 (d, 1H),7.42 (d, 2H), 7.36 (d, 1H), 7.26 (m, 1H), 7.16 (d, 2H), 6.78 (m, 1H),6.24 (d, 1H), 2.78 (d, 3H).

Step 5 Potassium(5-chlorothiophen-2-ylsulfonyl)(4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenylcarbamoyl)amide,7a

The 800L GL reactor number PP5-R1000 was charged with acetonitrile (134Kg), WFI quality water (156 Kg) and agitated the contents for 5 mins. Tothis then charged compound 6a (33.6 Kg, 1.0 equiv) and the reactionmixture was a suspension at this point. The suspension was charged withaqueous solution (WFI water, 35 Kg) of potassium hydroxide (4.14 Kg,1.15 equiv, >85%) at a rate that maintains the internal temperaturebelow 30° C. The charging lines were rinsed with WFI quality water (2Kg) followed by heating the 800L GL reactor contents to 50±5° C. for 1hr. The contents were then filtered hot through a bag filter, then aseven cartridge 0.2μ polish filter to clean HDPE drums. The hotfiltration system was maintained through out the filtration process sono material crashes out of the solution. Cool the 800L GL reactor jacketto 25±5° C. before proceeding to the reactor rinse. Rinsed the 800L GLreactor with pre-mixed solution of acetonitrile (8.5 Kg) and WFI qualitywater (10 Kg) through the filter system into the drums labeled as 7a hotfiltration. Using the pressure vessel the 800L GL reactor was rinsedwith WFI quality water (20 Kg) followed by acetone (20 Kg) then blow itdry with nitrogen (3+2 psig). The 800GL reactor bottom valve was closedand pulled 20+10 inches Hg of vacuum, then break the vacuum and chargethe reactor with the contents of the drums labeled as 7a hot filtration.Cooled the 800L GL reactor number PP5-R1000 contents to 20±5° C. andthen using a polish filter (PP-PF09), charged the reactor with methanol(373 kg, >99%) maintaining the internal temperature below 30oC. Thecontents of the 800GL reactor number PP5-R1000 were cooled to 15±5° C.followed by agitation of the contents for 12 hrs at this temperature.During this time the filterable solids were filtered through a cleanfilter apparatus (PP-F1000) into clean 200L GL receiver (PPR-04)followed by pressurizing the reactor, pulled 20+10 inches Hg of vacuumon the filter/receiver and filtered the contents. The filter cake waswashed with methanol (30 Kg) and blow dried with 8+7 psig of nitrogenfor 10 mins. The vacuum oven tray dryer temperature was set to 80° C.prior to loading the wet cake of 7a. Transferred the wet filter cakeinto the pre-lined vacuum trays with Dupont's fluorocarbon film—Kind100A and clamped down the special oven paper (Kavon MeI Tuf paper) overthe vacuum trays containing the product wet 7a and transferred to thevacuum oven tray dryer. Set the oven temperature to 80° C. and dry thewet 7a to a constant weight (constant weight is defined as tray readingat least 1 hr apart having the same weight within +50 g. Therepresentative sample was analyzed for residual solvents (residualsolvent specifications for API) and it met the specifications. The finalAPI was subjected to equilibration with water (5-6%) for 12 hrs with atray of WFI quality water present, then thoroughly turned and allowed tostand for an additional 12 hrs and finally subjected to KF analysis(5.5% water content). Transferred the 7-potassium (21.80 Kg, 60.6%yield) to double heavy-duty poly bags and stored in secondarycontainment. HPLC taken showed purity of 99.7% for 7a and ¹H NMRconfirmed the structure for 7a. ¹H NMR (DMSO): δ 11.14 (s, 1H), 8.60 (s,1H), 7.48 (m, 2H), 7.35 (d, 1H), 7.22 (d, 1H), 6.95 (m, 3H), 6.75 (m,1H), 6.22 (d, 1H), 2.78 (d, 3H).

Example 5 Pharmacological Assays

The pharmacological activity of each of the compounds according to theinvention is determined by the following in vitro assays:

I. Inhibition of ADP-Mediated Platelet Aggregation In Vitro

1.

The effect of testing the compound according to the invention onADP-induced human platelet aggregation was assessed in a 96-wellmicrotiter assay (see generally the procedures in Jantzen, H. M. et al.(1999) Thromb. Hemost. 81:111-117) or standard cuvette lighttransmittance aggregometry using either human platelet-rich plasma (PRP)or human washed platelets.

For preparation of human platelet-rich plasma for aggregation assays,human venous blood was collected from healthy, drug-free volunteers into0.38% sodium citrate (0.013 M, pH 7.0 final). Platelet-rich plasma (PRP)is prepared by centrifugation of whole blood at 160×g for 20 minutes atroom temperature. The PRP layer is removed, transferred to a new tube,and the platelet count is adjusted, if necessary, to achieve a plateletconcentration of ˜3×10⁸ platelets/ml using platelet-poor plasma (PPP).PPP is prepared by centrifugation of the remaining blood sample (afterremoval of PRP) for 20 minutes at 800×g. This preparation of PRP cansubsequently be used for aggregation assays in either a 96-well plate orstandard cuvette aggregometry.

For preparation of washed platelets, human venous blood is collectedfrom healthy, drug-free volunteers into ACD (85 mM sodium citrate, 111mM glucose, 71.4 mM citric acid) containing PGI₂ (1.25 ml ACD containing0.2 μM PGI2 final; PGI₂ was from Sigma, St. Louis, Mo.). Platelet-richplasma (PRP) is prepared by centrifugation at 160×g for 20 minutes atroom temperature. Washed platelets are prepared by centrifuging PRP for10 minutes at 730 g and resuspending the platelet pellet in CGS (13 mMsodium citrate, 30 mM glucose, 120 mM NaCl; 2 ml CGS/10 ml originalblood volume) containing 1 U/ml apyrase (grade V, Sigma, St. Louis,Mo.). After incubation at 37° C. for 15 minutes, the platelets arecollected by centrifugation at 730 g for 10 minutes and resuspended at aconcentration of 3×10⁸ platelets/ml in Hepes-Tyrode's buffer (10 mMHepes, 138 mM NaCl, 5.5 mM glucose, 2.9 mM KCl, 12 mM NaHCO₃, pH 7.4)containing 0.1% bovine serum albumin, 1 mM CaCl₂ and 1 mM MgCl₂. Thisplatelet suspension is kept >45 minutes at 37° C. before use inaggregation assays.

2.

For cuvette light transmittance aggregation assays, serial dilutions(1:3) of test compounds were prepared in 100% DMSO in a 96 well V-bottomplate (final DMSO concentration in the cuvette was 0.6%). The testcompound (3 μl of serial dilutions in DMSO) was preincubated with PRPfor 30-45 seconds prior to initiation of aggregation reactions, whichwere performed in a ChronoLog aggregometer by addition of agonist (5 or10 μM ADP) to 490 μl of PRP at 37° C. In some cases, light transmittanceaggregometry was performed using 490 μL of washed platelets (prepared asdescribed above) at 37° C., and aggregation was initiated by addition of5 μM ADP and 0.5 mg/ml human fibrinogen (American Diagnostics, Inc.,Greenwich, Conn.). The aggregation reaction is recorded for ˜5 min, andmaximum extent of aggregation is determined by the difference in extentof aggregation at baseline, compared to the maximum aggregation thatoccurs during the five minute period of the assay. Inhibition ofaggregation was calculated as the maximum aggregation observed in thepresence of inhibitor, compared to that in the absence of inhibitor.IC₅₀s were derived by non-linear regression analysis using the Prismsoftware (GraphPad, San Diego, Calif.).

3.

Inhibition of ADP-dependent aggregation was also determined in 96-wellflat-bottom microtiter plates using a microtiter plate shaker and platereader similar to the procedure described by Frantantoni et al., Am. J.Clin. Pathol. 94, 613 (1990). All steps are performed at roomtemperature. For 96-well plate aggregation using platelet-rich plasma(PRP), the total reaction volume of 0.2 ml/well includes 180 μl of PRP(˜3×108 platelets/ml, see above), 6 μl of either serial dilution of testcompounds in 20% DMSO or buffer (for control wells), and 10 μl of 20×ADPagonist solution (100 μM). The OD of the samples is then determined at450 nm using a microtiter plate reader (Softmax, Molecular Devices,Menlo Park, Calif.) resulting in the 0 minute reading. The plates arethen agitated for 5 min on a microtiter plate shaker and the 5 minutereading is obtained in the plate reader. Aggregation is calculated fromthe decrease of OD at 450 nm at t=5 minutes compared to t=0 minutes andis expressed as % of the decrease in the ADP control samples aftercorrecting for changes in the unaggregated control samples. IC₅₀s werederived by non-linear regression analysis.

For 96-well plate aggregation using washed platelets, the total reactionvolume of 0.2 ml/well includes in Hepes-Tyrodes buffer/0.1% BSA: 4.5×10⁷apyrase-washed platelets, 0.5 mg/ml human fibrinogen (AmericanDiagnostica, Inc., Greenwich, Conn.), serial dilutions of test compounds(buffer for control wells) in 0.6% DMSO. After ˜5 minutes preincubationat room temperature, ADP is added to a final concentration of 2 μM whichinduces submaximal aggregation. Buffer is added instead of ADP to oneset of control wells (ADP-control). The OD of the samples is thendetermined at 450 nm using a microtiter plate reader (Softmax, MolecularDevices, Menlo Park, Calif.) resulting in the 0 minute reading. Theplates are then agitated for 5 min on a microtiter plate shaker and the5 minute reading is obtained in the plate reader. Aggregation iscalculated from the decrease of OD at 450 nm at t=5 minutes compared tot=0 minutes and is expressed as % of the decrease in the ADP controlsamples after correcting for changes in the unaggregated controlsamples. IC₅₀s were derived by non-linear regression analysis.

II. Inhibition of [3H]2-MeS-ADP Binding to Platelets

1. The ability of candidate molecules to inhibit the binding of[3H]2-MeS-ADP to the P2Y12 receptor on platelets was determined using aradioligand binding assay.

Utilizing this assay the potency of inhibition of such compounds withrespect to [³H]2-MeS-ADP binding to whole platelets is determined. Underthe conditions described in II (3) below, the binding of [³H]2-MeS-ADPis solely due to the interaction of this ligand with the P2Y₁₂ receptor,in that all the specific binding measured in this assay is competablewith a P2Y₁₂ antagonist (i.e., the specific binding is reduced tobackground levels by competition with an excess of P2Y₁₂ antagonist,with no competition of binding when a P2Y₁ antagonist is pre-incubatedwith the platelet preparation). [³H]2-MeS-ADP binding experiments areroutinely performed with outdated human platelets collected by standardprocedures at hospital blood banks. Apyrase-washed outdated plateletsare prepared as follows (all steps at room temperature, if not indicatedotherwise):

Outdated platelet suspensions are diluted with 1 volume of CGS andplatelets pelleted by centrifugation at 1900×g for 45 minutes. Plateletpellets are resuspended at 3-6×10⁹ platelets/ml in CGS containing 1 U/mlapyrase (grade V, Sigma, St. Louis, Mo.) and incubated for 15 minutes at37° C. After centrifugation at 730×g for 20 minutes, pellets areresuspended in Hepes-Tyrode's buffer containing 0.1% BSA (Sigma, St.Louis, Mo.) at a concentration of 6.66×10⁸ platelets/ml. Bindingexperiments are performed after >45 minutes resting of the platelets.

2.

Alternatively, binding experiments are performed with fresh humanplatelets prepared as described in section I (Inhibition of ADP-MediatedPlatelet Aggregation in vitro), except that platelets are resuspended inHepes-Tyrode's buffer containing 0.1% BSA (Sigma, St. Louis, Mo.) at aconcentration of 6.66×10⁸ platelets/mil. Very similar results areobtained with fresh and outdated platelets.

3.

A platelet ADP receptor binding assay (ARB) using the tritiated potentagonist ligand [³H]2-MeS-ADP (Jantzen, H. M. et al. (1999) Thromb.Hemost. 81:111-117) has been adapted to the 96-well microtiter format.In an assay volume of 0.2 ml Hepes-Tyrode's buffer with 0.1% BSA and0.6% DMSO, 1×10⁸ apyrase-washed platelets are preincubated in 96-wellflat bottom microtiter plates for 5 minutes with serial dilutions oftest compounds before addition of 1 nM [³H]2-MeS-ADP([³H]2-methylthioadenosine-5′-diphosphate, ammonium salt; specificactivity 20-50 Ci/mmole, obtained by custom synthesis from Amersham LifeScience, Inc., Arlington Heights, Ill., or NEN Life Science Products,Boston, Mass.). Total binding is determined in the absence of testcompounds. Samples for nonspecific binding may contain 100M unlabelled2-MeS-ADP (RBI, Natick, Mass.). After incubation for 15 minutes at roomtemperature, unbound radioligand is separated by rapid filtration andtwo washes with cold (4-8° C.) Binding Wash Buffer (10 mM Hepes pH 7.4,138 mM NaCl) using a 96-well cell harvester (Minidisc 96, SkatronInstruments, Sterling, Va.) and 8×12 GF/C glassfiber filtermats (PrintedFiltermat A, for 1450 Microbeta, Wallac Inc., Gaithersburg, Md.). Theplatelet-bound radioactivity on the filtermats is determined in ascintillation counter (Microbeta 1450, Wallac Inc., Gaithersburg, Md.).Specific binding is determined by subtraction of non-specific bindingfrom total binding, and specific binding in the presence of testcompounds is expressed as % of specific binding in the absence of testcompound dilutions. IC₅₀s were derived by non-linear regressionanalysis.

In the table below, activity in the PRP assay is provided as follows:+++, IC₅₀<10 μM; ++, 10 μM<IC₅₀<30 μM. Activity in the ARB assay isprovided as follows: +++, IC₅₀<0.05 μM; ++, 0.05 μM <IC₅₀<0.5 μM.

TABLE 5 Example No. ARB Binding PRP Activity Example 2 +++ +++ Example 3++ ++

Example 6 Synthesis of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureapotassium salt (9a) (amorphous form)

The free-acid, sulfonylurea, (7.0 g, 13.365 mmol) was suspended inTHF/H₂O (55:22 mL, ca. 2.5:1), and treated with 2M KOH (7.70 mL, 15.40mmol, 1.15 equiv) drop wise, over ca. 5 min. By the time the additionwas over, a clear solution resulted. But, then soon after (<5 mins), asolid precipitated out and reaction mixture became a heavy suspension.This was heated in an oil-bath to 50° C., and the resulting clearviscous light brown solution was held there for 0.5 h. On cooling tort., the title compound precipitated out. The mixture was diluted withi-PrOH (250 mL, 3× the original reaction volume), stirred at rt. for 3h, and then filtered through a Buchner funnel to yield the titlecompound as a colorless solid. This was dried in a vacuum oven at 80° C.to yield 7.20 g (96%) of an amorphous solid. MS (negative scan): 521.7;523.7.

Example 7 Conversion of the sulfonylurea (7a) to its sodium salt (10a)

1-(5-chlorothiophen-2-ylsulfonyl)-3-(4-(6-fluoro-7-(methylamino)-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)urea(3.0 g, 5.728 mmol) 7a was suspended in CH₃CN/H₂O) (1:1; 70 mL) and wastreated with 2N NaOH (2.90 mL, 5.80 mmol), dropwise. Within ca. 15minutes, a clear solution resulted. After stirring for 1.0 h, the nowlight brown solution was lyophilized to afford the crude product as anamorphous solid 10a. MS (negative scan): 522.0; 524.0.

Example 8 Preparation of Amorphous Form of the Sodium Salt

Sodium salt 10b was suspended in isopropanol (100 mL) and refluxed forca. 45 min, then hot filtered to yield a tan solid, which is mostly thetitle compound by HPLC. The tan solid was suspended in CH₃CN:EtOH (1:2)(100 mL) and refluxed for 45 mins., then hot filtered to afford 2.54 gof the title compound as a tan solid (99.6887% pure by analytical HPLC,long column). The filtrate was diluted with EtOH until the ratio ofACN:EtOH became (1:3) and then let stand at room temperature overnightwhen the title compound precipitated out to afford 210 mg of the titlecompound (purity: 99.6685% by analytical HPLC, long column).

Example 9 Preparation of Polymorph Form a of Potassium Salt byRecrystallization

Recrystallization: The crude product can be recrystallized either fromMeOH or MeOH/EtOH (3:1) by first heating to reflux to dissolve, and thencooling to room temperature to precipitate.

Recrystallization From MeOH: 1.0 g of the potassium salt was suspendedin MeOH (150 mL) and heated to reflux for 0.5 h, resulting in an almostclear solution. This was then hot filtered through a Buchner funnel. Theclear filtrate on standing at room temperature deposited a colorlesssolid. This was stirred overnight and then collected by filtrationthrough a Buchner funnel. The solid product was rinsed with EtOH (2×4.0mL) and dried in a vacuum oven at 80° C. for 20 h to yield 740 mg of acolorless solid. The mother liquor yielded more title compound onconcentration to ca. one-third of the original volume.

Recrystallization from EtOH/MeOH: 1.0 g of the potassium salt wassuspended in the solvent mixture EtOH/MeOH (1:3) (200 mL), and heated toreflux for 0.5 h resulting in an almost clear solution. This was thenhot filtered through a Buchner funnel. The clear filtrate on standing atroom temperature deposited a colorless solid. This was collected byfiltration through a Buchner funnel. The solid product was rinsed withEtOH and dried in vacuum oven at 80° C. for 20 h to give a colorlesssolid. The mother liquor yielded more title compound upon concentrationto ca. one-third of the original volume.

Example 10 Preparation of Polymorph Form B of Potassium Salt byRecrystallization

Recrystallization: The crude product can be recrystallized from EtOH/H₂O(91:9) or a small volume of MeOH by first heating to reflux to dissolve,and then cooling to room temperature to precipitate.

Recrystallization from EtOH/H₂O: 1.0 g of the potassium salt wassuspended in EtOH (190 mL) and heated to reflux. To the heavy suspensionwas added H₂O (18.0 mL) dropwise, resulting in a clear colorlesssolution. On cooling to room temperature, the title compoundprecipitated out as a colorless solid. It was collected by filtrationthrough a Buchner funnel, and rinsed with EtOH (2×4.0 mL). This wasdried in vacuum oven at 80° C. for 20 h, to give 650 mg of a colorlesssolid. The mother liquor yielded more title compound upon concentrationto ca. one-third of the original volume.

Large Scale Recrystallization from small volume of MeOH: 6.6 g of thepotassium salt was suspended in MeOH (30 mL) and heated to reflux for 5hr, the solid did not completely dissolve in less volume of methanol.After cooling the solid was filtered and rinsed with iPrOH. This wasdried in vacuum oven at 80° C. for 20 h, to give 6.2 g of colorlesssolid, characterized to be Form B.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, one of skill in the art will appreciate that certainchanges and modifications may be practiced within the scope of theappended claims. In addition, each reference provided herein isincorporated by reference in its entirety to the same extent as if eachreference was individually incorporated by reference.

1. A method for preventing or treating thrombosis and thrombosis relatedconditions in a mammal comprising the step of administering to a mammala therapeutically effective amount of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureahaving the following formula:

or a pharmaceutically acceptable salt or hydrate thereof.
 2. A methodfor preventing or treating a condition or disorder mediated at least inpart by ADP-induced platelet aggregation in a mammal comprising the stepof administering to a mammal in need of such treatment in atherapeutically effective amount of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureahaving the following formula:

or a pharmaceutically acceptable salt or hydrate thereof.
 3. The methodof claim 2, wherein said mammal is prone to or suffers from acardiovascular disease.
 4. The method of claim 3, wherein saidcardiovascular disease is at least one selected from the groupconsisting of acute myocardial infarction, unstable angina, chronicstable angina, transient ischemic attacks, strokes, peripheral vasculardisease, preeclampsia/eclampsia, deep venous thrombosis, embolism,disseminated intravascular coagulation and thrombotic cytopenic purpura,thrombotic and retenotic complications following invasive proceduresresulting from angioplasty, carotid endarterectorny, post CABG (coronaryartery bypass graft) surgery, vascular gram surgery, stent, in-stentthrombosis, and insertion of endovascular devices and prostheses, andhypercoagulable states related to genetic predisposition or cancers. 5.The method of claim 1, wherein the compound is administered orally,parenterally or topically.
 6. The method of claim 1, wherein thecompound is administered in combination with a second therapeutic agent.7. The method of claim 6, wherein the patient is a human.
 8. The methodof claim 6, wherein the second therapeutic agent is useful for treatinga condition or disorder selected from the group consisting of acutemyocardial infarction, unstable angina, chronic stable angina, transientischemic attacks, strokes, peripheral vascular disease,preeclampsia/eclampsia, deep venous thrombosis, embolism, disseminatedintravascular coagulation and thrombotic cytopenic purpura, thromboticand restenotic complications following invasive procedures resultingfrom angioplasty, carotid endarterectorny, post CABG (coronary arterybypass graft) surgery, vascular gram surgery, stent placements andinsertion of endovascular devices, prostheses, and hypercoagulablestates related to genetic predisposition and cancer.
 9. The method inaccordance with claim 6, wherein said compound is administered incombination with a second therapeutic agent selected from the groupconsisting of antiplatelet compounds, anticoagulants, fibrinolytics,anti-inflammatory compounds, cholesterol-lowering agents, proton pumpinhibitors, blood pressure-lowering agents, serotonin blockers, andnitrates.
 10. The method in accordance with claim 9, wherein said secondtherapeutic agent is an antiplatelet compound selected from the groupconsisting of GPIIB-IIIa antagonists, aspirin, phosphodiesterase IIIinhibitors and thromboxane A2 receptor antagonists.
 11. The method inaccordance with claim 9, wherein said second therapeutic agent is ananticoagulant selected from the group consisting of thrombin inhibitors,coumadin, heparin, and fXa inhibitors.
 12. The method in accordance withclaim 9, wherein said second therapeutic agent is an anti-inflammatorycompound selected from the group consisting of non-steroidalanti-inflammatory agents, cyclooxygenase-2 inhibitors and rheumatoidarthritis agents.
 13. A method for preventing the occurrence of asecondary ischemic event comprising administering to a patient who hassuffered a primary ischemic event a therapeutically effective amount of[4-(6-fluoro-7-methylamino-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-5-chloro-thiophen-2-yl-sulfonylureahaving the following formula:

or a pharmaceutically acceptable salt or hydrate thereof, together witha pharmaceutically acceptable carrier.
 14. The method in accordance withclaim 13, wherein said primary and/or secondary ischemic event isselected from the group consisting of myocardial infarction, stable orunstable angina, acute reocclusion after percutaneous coronaryintervention, and/or stenting, restenosis, peripheral vessel balloonangioplasty and/or stenting, thrombotic stroke, transient ischemicattack, reversible ischemic neurological deficit and intermittentclaudication.
 15. The method in accordance with claim 13, wherein saidprimary and/or secondary ischemic event is selected from the groupconsisting of percutaneous coronary intervention (PCI) includingangioplasty and/or stent, acute myocardial infarction (AMI), unstableangina (USA), coronary artery disease (CAD), transient ischemic attacks(TIA), stroke, peripheral vascular disease (PVD), Surgeries-coronarybypass, carotid endarectomy.